Posts Tagged ‘Genome-wide association study’

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation: a Compilation of Articles in the Journal http://pharmaceuticalintelligence.com

Compilation of References by Leaders in Pharmaceutical Business Intelligence in the Journal http://pharmaceuticalintelligence.com about
Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation

Curator: Larry H Bernstein, MD, FCAP


  1. The Human Proteome Map Completed

Reporter and Curator: Larry H. Bernstein, MD, FCAP


  1. Proteomics – The Pathway to Understanding and Decision-making in Medicine

Author and Curator, Larry H Bernstein, MD, FCAP


3. Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-         of-therapeutic-targets/

  1. Expanding the Genetic Alphabet and Linking the Genome to the Metabolome

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-                metabolome/

5. Genomics, Proteomics and standards

Larry H Bernstein, MD, FCAP, Author and Curator


6. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Author and Curator




  1. Extracellular evaluation of intracellular flux in yeast cells

Larry H. Bernstein, MD, FCAP, Reviewer and Curator


  1. Metabolomic analysis of two leukemia cell lines. I.

Larry H. Bernstein, MD, FCAP, Reviewer and Curator


  1. Metabolomic analysis of two leukemia cell lines. II.

Larry H. Bernstein, MD, FCAP, Reviewer and Curator


  1. Metabolomics, Metabonomics and Functional Nutrition: the next step in nutritional metabolism and biotherapeutics

Reviewer and Curator, Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/22/metabolomics-metabonomics-and-functional-nutrition-the-next-step-          in-nutritional-metabolism-and-biotherapeutics/

  1. Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

Larry H. Bernstein, MD, FCAP, Reviewer and curator

https://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-              metabolism-provides-homeomeostatic-regulation/

Metabolic Pathways

  1. Pentose Shunt, Electron Transfer, Galactose, more Lipids in brief

Reviewer and Curator: Larry H. Bernstein, MD, FCAP


  1. Mitochondria: More than just the “powerhouse of the cell”

Ritu Saxena, PhD


  1. Mitochondrial fission and fusion: potential therapeutic targets?

Ritu saxena


4.  Mitochondrial mutation analysis might be “1-step” away

Ritu Saxena


  1. Selected References to Signaling and Metabolic Pathways in PharmaceuticalIntelligence.com

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/14/selected-references-to-signaling-and-metabolic-pathways-in-                     leaders-in-pharmaceutical-intelligence/

  1. Metabolic drivers in aggressive brain tumors

Prabodh Kandal, PhD


  1. Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

Writer and Curator, Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic-                        information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/

  1. Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation

Larry H Bernstein, MD, FCAP, author and curator

https://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-            glycolysis-metabolic-adaptation/

  1. Therapeutic Targets for Diabetes and Related Metabolic Disorders

Reporter, Aviva Lev-Ari, PhD, RD


10.  Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

Larry H. Bernstein, MD, FCAP, Reviewer and curator

https://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-              metabolism-provides-homeomeostatic-regulation/

11. The multi-step transfer of phosphate bond and hydrogen exchange energy

Larry H. Bernstein, MD, FCAP, Curator:

https://pharmaceuticalintelligence.com/2014/08/19/the-multi-step-transfer-of-phosphate-bond-and-hydrogen-                          exchange-energy/

12. Studies of Respiration Lead to Acetyl CoA


13. Lipid Metabolism

Author and Curator: Larry H. Bernstein, MD, FCAP


14. Carbohydrate Metabolism

Author and Curator: Larry H. Bernstein, MD, FCAP


15. Update on mitochondrial function, respiration, and associated disorders

Larry H. Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-                   disorders/

16. Prologue to Cancer – e-book Volume One – Where are we in this journey?

Author and Curator: Larry H. Bernstein, MD, FCAP


17. Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research-          how-we-got-here/

18. Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K

Author and Curator: Larry H. Bernstein, MD, FCAP


19. The Binding of Oligonucleotides in DNA and 3-D Lattice Structures

Author and Curator: Larry H. Bernstein, MD, FCAP


20. Mitochondrial Metabolism and Cardiac Function

Author and Curator: Larry H. Bernstein, MD, FCAP


21. How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

Curator: Larry H. Bernstein, MD, FCAP


22. AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

Author and Curator: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2013/03/12/ampk-is-a-negative-regulator-of-the-warburg-effect-and-suppresses-         tumor-growth-in-vivo/

23. A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-                         conundrum/

24. Mitochondrial Damage and Repair under Oxidative Stress

Author and Curator: Larry H. Bernstein, MD, FCAP


25. Nitric Oxide and Immune Responses: Part 2

Author and Curator: Aviral Vatsa, PhD, MBBS


26. Overview of Posttranslational Modification (PTM)

Writer and Curator: Larry H. Bernstein, MD, FCAP


27. Malnutrition in India, high newborn death rate and stunting of children age under five years

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/15/malnutrition-in-india-high-newborn-death-rate-and-stunting-of-                   children-age-under-five-years/

28. Update on mitochondrial function, respiration, and associated disorders

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-                  disorders/

29. Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency-         in-renal-disease/

30. Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Larry H. Bernstein, MD, FCAP, writer, and Aviva Lev- Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/27/larryhbernintroduction_to_cardiovascular_diseases-                                  translational_medicine-part_2/

31. Epilogue: Envisioning New Insights in Cancer Translational Biology
Series C: e-Books on Cancer & Oncology

Author & Curator: Larry H. Bernstein, MD, FCAP, Series C Content Consultant


32. Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone                         and Neurotransmitter

Writer and Curator: Larry H Bernstein, MD, FCAP and
Curator and Content Editor: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-                    hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocy

33. Cardiac Contractility & Myocardial Performance: Therapeutic Implications of Ryanopathy (Calcium Release-                           related Contractile Dysfunction) and Catecholamine Responses

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC
Author and Curator: Larry H Bernstein, MD, FCAP
and Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-      and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-                    contractile/

34. Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Author and Curator: Larry H Bernstein, MD, FCAP Author: Stephen Williams, PhD, and Curator: Aviva Lev-Ari, PhD, RN


35. Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-                           cytoskeleton/

36. Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its-              End-Stage/

37. The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

Demet Sag, PhD, Author and Curator

https://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-               immunology/

38. IDO for Commitment of a Life Time: The Origins and Mechanisms of IDO, indolamine 2, 3-dioxygenase

Demet Sag, PhD, Author and Curator

https://pharmaceuticalintelligence.com/2013/08/04/ido-for-commitment-of-a-life-time-the-origins-and-mechanisms-of-             ido-indolamine-2-3-dioxygenase/

39. Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

Curator: Demet Sag, PhD, CRA, GCP

https://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis-           of-immune-responses-for-good-and-bad/

40. Signaling Pathway that Makes Young Neurons Connect was discovered @ Scripps Research Institute

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/26/signaling-pathway-that-makes-young-neurons-connect-was-                     discovered-scripps-research-institute/

41. Naked Mole Rats Cancer-Free

Writer and Curator: Larry H. Bernstein, MD, FCAP


42. Late Onset of Alzheimer’s Disease and One-carbon Metabolism

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


43. Problems of vegetarianism

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


44.  Amyloidosis with Cardiomyopathy

Writer and Curator: Larry H. Bernstein, MD, FCAP


45. Liver endoplasmic reticulum stress and hepatosteatosis

Larry H Bernstein, MD, FACP


46. The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

Curator and Author: Larry H Bernstein, MD, FACP


47. Nitric Oxide Function in Coagulation – Part II

Curator and Author: Larry H. Bernstein, MD, FCAP


48. Nitric Oxide, Platelets, Endothelium and Hemostasis

Curator and Author: Larry H Bernstein, MD, FACP


49. Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Curator and Author: Larry H Bernstein, MD, FACP


50. Nitric Oxide and Immune Responses: Part 1

Curator and Author:  Aviral Vatsa PhD, MBBS


51. Nitric Oxide and Immune Responses: Part 2

Curator and Author:  Aviral Vatsa PhD, MBBS


52. Mitochondrial Damage and Repair under Oxidative Stress

Curator and Author: Larry H Bernstein, MD, FACP


53. Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-                 century-view/

54. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                  proteolysis-and-cell-apoptosis/

55. Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                   proteolysis-and-cell-apoptosis-reconsidered/

56. Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

Curator and Author: Larry H Bernstein, MD, FACP


57. New Insights on Nitric Oxide donors – Part IV

Curator and Author: Larry H Bernstein, MD, FACP


58. Crucial role of Nitric Oxide in Cancer

Curator and Author: Ritu Saxena, Ph.D.


59. Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-         a-concomitant-influence-on-mitochondrial-function/

60. Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

Curator and Author: Ziv Raviv, PhD, RN 04/06/2013


61. Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I

Curator and Author: Larry H Bernstein, MD, FACP


Genomics, Transcriptomics, and Epigenetics

  1. What is the meaning of so many RNAs?

Writer and Curator: Larry H. Bernstein, MD, FCAP


  1. RNA and the transcription the genetic code

Larry H. Bernstein, MD, FCAP, Writer and Curator


  1. A Primer on DNA and DNA Replication

Writer and Curator: Larry H. Bernstein, MD, FCAP


4. Synthesizing Synthetic Biology: PLOS Collections

Reporter: Aviva Lev-Ari


5. Pathology Emergence in the 21st Century

Author and Curator: Larry Bernstein, MD, FCAP


6. RNA and the transcription the genetic code

Writer and Curator, Larry H. Bernstein, MD, FCAP


7. A Great University engaged in Drug Discovery: University of Pittsburgh

Larry H. Bernstein, MD, FCAP, Reporter and Curator


8. microRNA called miRNA-142 involved in the process by which the immature cells in the bone  marrow give                              rise to all the types of blood cells, including immune cells and the oxygen-bearing red blood cells

Aviva Lev-Ari, PhD, RN, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/24/microrna-called-mir-142-involved-in-the-process-by-which-the-                   immature-cells-in-the-bone-marrow-give-rise-to-all-the-types-of-blood-cells-including-immune-cells-and-the-oxygen-             bearing-red-blood-cells/

9. Genes, proteomes, and their interaction

Larry H. Bernstein, MD, FCAP, Writer and Curator


10. Regulation of somatic stem cell Function

Larry H. Bernstein, MD, FCAP, Writer and Curator    Aviva Lev-Ari, PhD, RN, Curator


11. Scientists discover that pluripotency factor NANOG is also active in adult organisms

Larry H. Bernstein, MD, FCAP, Reporter

https://pharmaceuticalintelligence.com/2014/07/10/scientists-discover-that-pluripotency-factor-nanog-is-also-active-in-           adult-organisms/

12. Bzzz! Are fruitflies like us?

Larry H Bernstein, MD, FCAP, Author and Curator


13. Long Non-coding RNAs Can Encode Proteins After All

Larry H Bernstein, MD, FCAP, Reporter


14. Michael Snyder @Stanford University sequenced the lymphoblastoid transcriptomes and developed an
allele-specific full-length transcriptome

Aviva Lev-Ari, PhD, RN, Author and Curator

https://pharmaceuticalintelligence.com/014/06/23/michael-snyder-stanford-university-sequenced-the-lymphoblastoid-            transcriptomes-and-developed-an-allele-specific-full-length-transcriptome/

15. Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: Views by Larry H                                     Bernstein, MD, FCAP

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/16/commentary-on-biomarkers-for-genetics-and-genomics-of-                        cardiovascular-disease-views-by-larry-h-bernstein-md-fcap/

16. Observations on Finding the Genetic Links in Common Disease: Whole Genomic Sequencing Studies

Author an curator: Larry H Bernstein, MD, FCAP


17. Silencing Cancers with Synthetic siRNAs

Larry H. Bernstein, MD, FCAP, Reviewer and Curator


18. Cardiometabolic Syndrome and the Genetics of Hypertension: The Neuroendocrine Transcriptome Control Points

Reporter: Aviva Lev-Ari, PhD, RN


19. Developments in the Genomics and Proteomics of Type 2 Diabetes Mellitus and Treatment Targets

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2013/12/08/developments-in-the-genomics-and-proteomics-of-type-2-diabetes-           mellitus-and-treatment-targets/

20. Loss of normal growth regulation

Larry H Bernstein, MD, FCAP, Curator


21. CT Angiography & TrueVision™ Metabolomics (Genomic Phenotyping) for new Therapeutic Targets to Atherosclerosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/15/ct-angiography-truevision-metabolomics-genomic-phenotyping-for-           new-therapeutic-targets-to-atherosclerosis/

22.  CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

Genomics Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/30/cracking-the-code-of-human-life-the-birth-of-bioinformatics-                      computational-genomics/

23. Big Data in Genomic Medicine

Author and Curator, Larry H Bernstein, MD, FCAP


24. From Genomics of Microorganisms to Translational Medicine

Author and Curator: Demet Sag, PhD

https://pharmaceuticalintelligence.com/2014/03/20/without-the-past-no-future-but-learn-and-move-genomics-of-                      microorganisms-to-translational-medicine/

25. Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author and Curator, Larry H Bernstein, MD, FCAP


 26. Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious                      Depression

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/02/19/genomic-promise-for-neurodegenerative-diseases-dementias-autism-        spectrum-schizophrenia-and-serious-depression/

 27.  BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Sudipta Saha, PhD

https://pharmaceuticalintelligence.com/2012/12/04/brca1-a-tumour-suppressor-in-breast-and-ovarian-cancer-functions-         in-transcription-ubiquitination-and-dna-repair/

28. Personalized medicine gearing up to tackle cancer

Ritu Saxena, PhD


29. Differentiation Therapy – Epigenetics Tackles Solid Tumors

Stephen J Williams, PhD


30. Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

     Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/17/mechanism-involved-in-breast-cancer-cell-growth-function-in-early-          detection-treatment/

31. The Molecular pathology of Breast Cancer Progression

Tilde Barliya, PhD


32. Gastric Cancer: Whole-genome reconstruction and mutational signatures

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-                   signatures-2/

33. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine –                                                       Part 1 (pharmaceuticalintelligence.com)

Aviva  Lev-Ari, PhD, RN


34. LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer                                         Personalized Treatment: Part 2

A Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-       drug-selection-in-cancer-personalized-treatment-part-2/

35. Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-        research-part-3/

36. Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of                           Cancer Scientific Leaders @http://pharmaceuticalintelligence.com

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/7000/Harnessing_Personalized_Medicine_for_ Cancer_Management-      Prospects_of_Prevention_and_Cure/

37.  GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico
effect of the inhibitor in its “virtual clinical trial”

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/14/gsk-for-personalized-medicine-using-cancer-drugs-needs-alacris-             systems-biology-model-to-determine-the-in-silico-effect-of-the-inhibitor-in-its-virtual-clinical-trial/

38. Personalized medicine-based cure for cancer might not be far away

Ritu Saxena, PhD


39. Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/24/human-variome-project-encyclopedic-catalog-of-sequence-variants-         indexed-to-the-human-genome-sequence/

40. Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/10/inspiration-from-dr-maureen-cronins-achievements-in-applying-                genomic-sequencing-to-cancer-diagnostics/

41. The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-         of-dna-wcrick-41953/

42. What can we expect of tumor therapeutic response?

Author and curator: Larry H Bernstein, MD, FACP


43. Directions for genomics in personalized medicine

Author and Curator: Larry H. Bernstein, MD, FCAP


44. How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Stephen J Williams, PhD

https://pharmaceuticalintelligence.com/2012/10/31/how-mobile-elements-in-junk-dna-prote-cancer-part1-transposon-            mediated-tumorigenesis/

45. mRNA interference with cancer expression

Author and Curator, Larry H. Bernstein, MD, FCAP


46. Expanding the Genetic Alphabet and linking the genome to the metabolome

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-               metabolome/

47. Breast Cancer, drug resistance, and biopharmaceutical targets

Author and Curator: Larry H Bernstein, MD, FCAP


48.  Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression                            Analysis

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/12/24/breast-cancer-genomic-profiling-to-predict-survival-combination-of-           histopathology-and-gene-expression-analysis

49. Gastric Cancer: Whole-genome reconstruction and mutational signatures

Aviva  Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-                   signatures-2/

50. Genomic Analysis: FLUIDIGM Technology in the Life Science and Agricultural Biotechnology

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/08/22/genomic-analysis-fluidigm-technology-in-the-life-science-and-                   agricultural-biotechnology/

51. 2013 Genomics: The Era Beyond the Sequencing Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Aviva Lev-Ari, PhD, RD


52. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/Paradigm Shift in Human Genomics_/

Signaling Pathways

  1. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Curator


  1. A Synthesis of the Beauty and Complexity of How We View Cancer:
    Cancer Volume One – Summary

Author and Curator: Larry H. Bernstein, MD, FCAP


  1. Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in
    serous endometrial tumors

Sudipta Saha, PhD

https://pharmaceuticalintelligence.com/2012/11/19/recurrent-somatic-mutations-in-chromatin-remodeling-ad-ubiquitin-           ligase-complex-genes-in-serous-endometrial-tumors/

4.  Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Stephen J Williams, PhD

https://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-              transition-in-prostate-cancer-cells/

5. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                   proteolysis-and-cell-apoptosis/

6. Signaling and Signaling Pathways

Larry H. Bernstein, MD, FCAP, Reporter and Curator


7.  Leptin signaling in mediating the cardiac hypertrophy associated with obesity

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/11/03/leptin-signaling-in-mediating-the-cardiac-hypertrophy-associated-            with-obesity/

  1. Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP, Reporter and Curator


  1. The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis and Novel

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/10/15/the-final-considerations-of-the-role-of-platelets-and-platelet-                      endothelial-reactions-in-atherosclerosis-and-novel-treatments

10.   Platelets in Translational Research – Part 1

Larry H. Bernstein, MD, FCAP, Reporter and Curator


11.  Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and
Cardiovascular Calcium Signaling Mechanism

Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to e-SERIES A:
Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-             smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

12. The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and
Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia,
Similarities and Differences, and Pharmaceutical Targets

     Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to
e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and
Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-       kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-           differen/

13.  Nitric Oxide Signalling Pathways

Aviral Vatsa, PhD, MBBS


14. Immune activation, immunity, antibacterial activity

Larry H. Bernstein, MD, FCAP, Curator


15.  Regulation of somatic stem cell Function

Larry H. Bernstein, MD, FCAP, Writer and Curator    Aviva Lev-Ari, PhD, RN, Curator


16. Scientists discover that pluripotency factor NANOG is also active in adult organisms

Larry H. Bernstein, MD, FCAP, Reporter


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Blood Pressure Response to Antihypertensives: Hypertension Susceptibility Loci Study

Reporter: Aviva Lev-Ari, PhD, RN


Hypertension Susceptibility Loci and Blood Pressure Response to Antihypertensives

Results From the Pharmacogenomic Evaluation of Antihypertensive Responses Study

Yan Gong, PhD, Caitrin W. McDonough, PhD, Zhiying Wang, MS, Wei Hou, PhD,Rhonda M. Cooper-DeHoff, PharmD, MS, Taimour Y. Langaee, PhD, Amber L. Beitelshees, PharmD, MPH, Arlene B. Chapman, MD, John G. Gums, PharmD, Kent R. Bailey, PhD, Eric Boerwinkle, PhD, Stephen T. Turner, MD and Julie A. Johnson, PharmD

Author Affiliations

From the Department of Pharmacotherapy and Translational Research (Y.G., C.W.M., R.M.C.-D., T.Y.L., J.G.G., J.A.J.), Department of Biostatistics, College of Medicine (W.H.), Division of Cardiovascular Medicine, College of Medicine (R.M.C.-D., J.A.J.), and Department of Community Health and Family Medicine (J.G.G.), University of Florida, Gainesville, FL; Division of Epidemiology, University of Texas at Houston, Houston, TX (Z.W., E.B.); Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore, MD (A.L.B.); Renal Division, Emory University, Atlanta, GA (A.B.C.); and Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (S.T.T.).

Correspondence to Yan Gong, PhD, Department of Pharmacotherapy and Translational Research, University of Florida, PO Box 100486, 1600 SW Archer Rd, Gainesville, FL 32610. E-mail gong@cop.ufl.edu.


Background—To date, 39 single nucleotide polymorphisms (SNPs) have been associated with blood pressure (BP) or hypertension in genome-wide association studies in whites. Our hypothesis is that the loci/SNPs associated with BP/hypertension are also associated with BP response to antihypertensive drugs.

Methods and Results—We assessed the association of these loci with BP response to atenolol or hydrochlorothiazide monotherapy in 768 hypertensive participants in the Pharmacogenomics Responses of Antihypertensive Responses study. Linear regression analysis was performed on whites for each SNP in an additive model adjusting for baseline BP, age, sex, and principal components for ancestry. Genetic scores were constructed to include SNPs with nominal associations, and empirical Pvalues were determined by permutation test. Genotypes of 37 loci were obtained from Illumina 50K cardiovascular or Omni1M genome-wide association study chips. In whites, no SNPs reached Bonferroni-corrected α of 0.0014, 6 reached nominal significance (P<0.05), and 3 were associated with atenolol BP response at P<0.01. The genetic score of the atenolol BP-lowering alleles was associated with response to atenolol (P=3.3×10–6 for systolic BP; P=1.6×10–6 for diastolic BP). The genetic score of the hydrochlorothiazide BP-lowering alleles was associated with response to hydrochlorothiazide (P=0.0006 for systolic BP; P=0.0003 for diastolic BP). Both risk score P values were <0.01 based on the empirical distribution from the permutation test.

Conclusions—These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scoring.


Circulation: Cardiovascular Genetics.2012; 5: 686-691

Published online before print October 19, 2012,

doi: 10.1161/ CIRCGENETICS.112.964080


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Genomics of Incident Ischemic Stroke Events, Stroke and Cardiovascular Disease

Reporter: Aviva Lev-Ari, PhD, RN


Associations Between Incident Ischemic Stroke Events and Stroke and Cardiovascular Disease-Related Genome-Wide Association Studies Single Nucleotide Polymorphisms in the Population Architecture Using Genomics and Epidemiology Study

Cara L. Carty, PhD, Petra Bůžková, PhD, Myriam Fornage, PhD, Nora Franceschini, MD, Shelley Cole, PhD, Gerardo Heiss, MD, PhD, Lucia A. Hindorff, PhD, MPH, Barbara V. Howard, PhD, Sue Mann, MPH, Lisa W. Martin, MD, Ying Zhang, PhD, Tara C. Matise, PhD, Ross Prentice, PhD, Alexander P. Reiner, MD, MS and Charles Kooperberg, PhD

Author Affiliations

From the Public Health Sciences, Fred Hutchinson Cancer Research Center (C.L.C., S.M., R.P., C.K.); Department of Biostatistics, University of Washington, Seattle, WA (P.B.); Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX (M.F.); Division of Epidemiology, School of Public Health, University of Texas Health Sciences Center, Houston, TX (M.F.); Department of Epidemiology, University of North Carolina, Chapel Hill, NC (N.F., G.H.); Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX (S.C.); Office of Population Genomics, National Human Genome Research Institute, Bethesda, MD (L.A.H.); Medstar Health Research Institute, Washington, DC (B.V.H.); George Washington University School of Medicine, Washington, DC (B.V.H., L.W.M.); University of Oklahoma Health Sciences Center, Oklahoma City, OK (Y.Z.); Department of Genetics, Rutgers University, Piscataway, NJ (T.C.M.); Department of Epidemiology, University of Washington, Seattle, WA (A.P.R.).

Correspondence to Dr Cara L. Carty, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N./M3-A410, Seattle, WA 98109. E-mail ccarty@fhcrc.org


Background—Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different populations has been largely unexplored.

Methods and Results—Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein [HDL], low density lipoprotein [LDL], and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomicsand Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were associated with increased IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.

Conclusions—Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.


Circulation: Cardiovascular Genetics.2012; 5: 210-216


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Cardiovascular Genetics: Functional Characterization and Clinical Applications  @ 2013 Annual Conference of American Society of Human Genetics in Boston, 10/22-26, 2013

Reporter: Aviva Lev- Ari, PhD, RN

Sessions and Events 

The 63rd Annual Conference of American Society of Human Genetics in Boston, 10/22-26, 2013




We express a special interest in Session 58

Friday, October 25, 2013 Boston Convention Center 

2:00 PM–4:15 PM

Concurrent Platform (abstract-driven) Session E (54-62)

SESSION 58 – Cardiovascular Genetics: Functional Characterization and Clinical Applications

Room 205, Level 2, Convention Center

Moderators: Dan E. Arking, Johns Hopkins Univ. Sch. of Med.
Myriam Fornage, Univ. of Texas Hlth Sci. Ctr. at Houston

Human Syndromic Atrioventricular Septal Defect

367/2:00 A homozygous mutation in Smoothened, a member of the Sonic hedgehog (SHH)-GLI pathway is involved in human syndromic atrioventricular septal defect. W. S. Kerstjens-Frederikse, Y. Sribudiani, M. E. Baardman, L. M. A. Van Unen, R. Brouwer, M. van den Hout, C. Kockx, W. Van IJcken, A. J. Van Essen, P. A. Van Der Zwaag, G. J. Du Marchie Sarvaas, R. M. F. Berger, F. W. Verheijen, R. M. W. Hofstra.

A homozygous mutation in Smoothened, a member of the Sonic Hedgehog (SHH)-GLI pathway is involved in human syndromic atrioventricular septal defect.

W.S. Kerstjens-Frederikse1, Y. Sribudiani2, M.E. Baardman1, L.M.A. Van Unen2, R. Brouwer2, M. van den Hout2, C. Kockx2, W. Van IJcken2, A.J. Van Essen1, P.A. Van Der Zwaag1, G.J. Du Marchie

Sarvaas3, R.M.F. Berger3, F.W. Verheijen2, R.M.W. Hofstra2.

1) Dept Gen, Univ of Groningen, Univ Med Ctr Groningen, Netherlands;

2) Dept Gen, Erasmus Med Ctr, Rotterdam, Netherlands; 3) Dept Ped Cardiol, Univ of Groningen, Univ Med Ctr Groningen, Netherlands.

Introduction: Atrioventricular septal defect (AVSD) is a common congenital heart disease with a high impact on personal health. It is often accompanied by other congenital anomalies and in many of these syndromic AVSDs, defects in the sonic hedgehog (SHH)-GLI signalling pathway have been detected. SMO codes for the transmembrane protein smoothened (SMO), which is active in cells with a primary cilium and is located on the ciliary membrane. SMO is a key protein in the SHH-GLI signaling cascade.

Methods: Two probands, a twin boy and girl, presented with an AVSD, large fontanel, postaxial polydactyly and skin syndactyly of the second and third toes of both feet. The boy also had hypospadias. The parents were consanguineous and they had one healthy older child. Karyotyping was normal and Smith-Lemli-Opitz syndrome (SLOS) was excluded. Exome sequencing was performed and candidate variants were validated by Sanger sequencing.

Results: A novel homozygous missense mutation c.1725C>T (p.R575W) in SMO (7q32.3) was detected. Functional studies in fibroblasts of the patients showed normal expression of SMO protein but an abnormal localization of SMO, outside the cilia. Moreover we show severely reduced downstream GLI1 mRNA expression after stimulation with the SMO agonist purmorphamine. These results, together with the previously described association of SHH signalling defects with AVSD and SLOS, suggest that this SMO mutation is involved in syndromic AVSD in these patients.

Conclusion: We present the first reported smoothened mutation in humans, in two patients with an AVSD and a phenotype resembling Smith-Lemli-Opitz syndrome

Left Ventricular Noncompaction – Model in Zebrafish

368/2:15 Identification of PRDM16 as a disease gene for left ventricular non-compaction and the efficient generation of a personalized disease model in zebrafish. A.-K. Arndt, S. Schaefer, R. Siebert, S. A. Cook, H.-H. Kramer, S. Klaassen, C. A. MacRae.


Identification of PRDM16 as a disease gene for left ventricular noncompaction

and the efficient generation of a personalized disease

model in zebrafish. A.-K. Arndt1,2, S. Schaefer3, R. Siebert4, S.A. Cook5,

H.-H. Kramer2, S. Klaassen6, C.A. MacRae1. 

1) Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA;

2) Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig- Holstein, Kiel, Germany,;

3) Max-Delbruck-Center for Molecular Medicine, Berlin, Germany; 4) Institute of Human Genetics, University Hospital Schleswig Holstein, Kiel, Germany;

5) National Heart Centre, Singapore;

6) Department of Pediatric Cardiology, Charité, Berlin, Germany.

Using our own data and publically available array comparative genomic hybridization data, we identified the transcription factor PRDM16(PR domain containing 16) as a causal gene for the cardiomyopathy associated with monosomy 1p36, and confirmed its role in individuals with non-syndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). In a cohort of 75 non-syndromic patients with LVNC we detected 3 sporadic mutations, including 1 truncation mutant, 1 frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported non-synonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in over 6500 controls.

PRDM16 has not previously been associated with cardiovascular disease. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in impaired cardiomyocyte proliferation with associated physiologic defects in cardiac contractility and cell-cell coupling.

Using a phenotype-driven screening approach in the fish, we have identified 5 compounds that are able to rescue the physiologic defects associated with mutant or haploinsufficient PRDM16. Notably, all of the compounds had the capacity to restore cardiomyocyte proliferation and to prevent apoptosis in the model. Wildtype zebrafish also demonstrated a significant increase in cardiomyocyte numbers after treatment with the compounds suggesting a pro-proliferative effect of the compounds. In addition, the compounds also rescued the contractile and electrical defects observed in these disease models. These findings underline the importance of personalized disease models for specific pathways, to accelerate the exploration of disease biology and the development of innovative therapeutic approaches.

Genetics of Cerebral Small Vessel Disease

369/2:30 Mutation and copy number variation of FOXC1 causes cerebral small vessel disease. C. R. French, S. Seshadri, A. L. Destefano, M. Fornage, D. J. Emery, M. Hofker, J. Fu, A. J. Waskiewicz, O. J. Lehmann.

Mutation and copy number variation of FOXC1 causes cerebral small vessel disease. C.R. French1, S. Seshadri2, A.L Destefano3, M. Fornage4, D.J. Emery5, M. Hofker6, J. Fu6, A.J. Waskiewicz7, O.J. Lehmann1, 8.

1) Ophthalmology, University of Alberta, Edmonton, AB, Canada;

2) Department of Neurology, Boston University, Boston, MA, U. S. A;

3) School of Public Health, Boston University, Boston, MA, U. S. A;

4) Institute of Molecular Medicine and School of Public Health, University of Texas Health Sciences

Center, Houston, TX, U.S.A;

5) Department of Radiology, University of Alberta, Edmonton, AB, Canada;

6) Department of Medical Genetics, University Medical Center Groningen, Groningen, The Netherlands;

7) Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada;

8) Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.

Cerebral small vessel disease (CSVD) represents a major risk factor for stroke and cognitive decline in the elderly. The ability to readily visualize its microangiopathic features by magnetic resonance imaging provides opportunities for using markers of CSVD to identify novel stroke associated pathways. Using targeted genome-wide association analysis we identified CSVD associated single nucleotide polymorphisms (SNPs) adjacent to the forkhead transcription factor FOXC1, and using eQTL analysis in two independent data sets, demonstrate that such SNP’s are associated with FOXC1 expression levels.

We further demonstrate, using magnetic resonance imaging, that patients with either FOXC1 mutation or copy number variation exhibit CSVD. These findings, present in patients as young as two years of age and observed with missense and nonsense mutations as well as FOXC1-encompassing segmental deletion and duplication, demonstrate FOXC1 dysfunction induces cerebral small vessel pathology. A causative role for FOXC1 in the development and maintenance of cerebral vasculature is supported by the cerebral hemorrhage generated by morpholino-induced suppression of FOXC1 orthologs in a zebrafish model system. Furthermore, in vivo imaging demonstrates profoundly impaired migration of neural crest cells and their subsequent association with nascent vasculature, a process required for the differentiation of perivascular mural cells. In addition, foxc1 inhibition reduces the expression of pdgfra, a gene critically required for vascular stability via its role in mural cell recruitment. Taken together, these data support a requirement for Foxc1 in stabilizing newly formed vasculature via recruitment of neural crest derived mural cells, and define a casual role for FOXC1 in cerebrovascular pathology.

Genetics & Brugada Syndrome

370/2:45 Genetic association of common variants with a rare cardiac disease, the Brugada syndrome, in a multi-centric study. C. Dina, J. Barc, Y. Mizusawa, C. A. Remme, J. B. Gourraud, F. Simonet, P. J. Schwartz, L. Crotti, P. Guicheney, A. Leenhardt, C. Antzelevitch, E. Schulze-Bahr, E. R. Behr, J. Tfelt-Hansen, S. Kaab, H. Watanabe, M. Horie, N. Makita, W. Shimizu, P. Froguel, B. Balkau, M. Gessler, D. Roden, V. M. Christoffels, H. Le Marec, A. A. Wilde, V. Probst, J. J. Schott, R. Redon, C. R. Bezzina.

Genetic association of common variants with a rare cardiac disease,

the Brugada Syndrome, in a multi-centric study. C. Dina1,2, J. Barc3, Y.

Mizusawa3, C.A. Remme3, J.B. Gourraud1,2, F. Simonet1, P.J. Schwartz4,

L. Crotti4, P. Guicheney5, A. Leenhardt6, C. Antzelevitch7, E. Schulze-Bahr8,

E.R. Behr9, J. Tfelt-Hansen10, S. Kaab11, H. Watanabe12, M. Horie13, N.

Makita14, W. Shimizu15, P. Froguel 16, B. Balkau17, M. Gessler18, D.

Roden19, V.M. Christoffels3, H. Le Marec1,2, A.A. Wilde3, V. Probst1,2, J.J.

Schott1,2, R. Redon1,2, C.R. Bezzina3.

1) Thorx Inst, INSERM UMR 1087, CNRS, Nantes, France;

2) CHU Nantes, l’institut du thorax, Nantes, France;

3) Heart Failure Research Center, Academic Medical Center, Amsterdam, Netherlands;

4) University of Pavia, Pavia, Italy;

5) InsermUMR956, UPMC, Paris, France;

6) Cardiology Unit, Hôpital Bichat, Assistance Publique- Hôpitaux de Paris, Nantes, France;

7) Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY, United States;

8) Department of Cardiovascular Medicine, University Hospital, Münster, Germany;

9) Cardiovascular Sciences Research Centre, St George’s University, London, United Kingdom;

10) Laboratory of Molecular Cardiology, University of Copenhagen, Copenhagen, Denmark;

11) 1Department of Medicine I, Ludwig-Maximilians University, Munich, Germany;

12) Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;

13) Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan;

14) Department of Molecular Physiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan;

15) Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan;

16) CNRS UMR 8199, Pasteur Institute, Lille, France;

17) Inserm UMR 1018, Centre for research in Epidemiology and Population Health, Villejuif, France;

18) Theodor-Boveri-Institute, University of Wuerzburg, Wuerzburg, Germany;

19) Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, United States.

The Brugada Syndrome (BrS) is considered as a rare Mendelian disorder with autosomal dominant transmission. BrS is associated with an increased risk of sudden cardiac death and specific electrocardiographic features consisting of ST-segment elevation in the right precordial leads. Loss-of-function mutations in SCN5A, encoding the pore-forming subunit of the cardiac sodium channel (Nav1.5), are identified in ~20% of patients. However, studies in families harbouring mutations in SCN5A have demonstrated low disease penetrance and in some instances absence of the familial SCN5A mutation in some affected members. These observations suggest a more complex inheritance model. To identify common genetic factors modulating disease risk, we conducted a genome-wide association study on 312 individuals with BrS and 1115 ancestry-matched controls. Two genomic regions displayed significant association. Both associations were replicated on two independent case/control sets from Europe (598/855) and Japan (208/1016) and a third locus emerged, all three with extremely significant p-values (1.10-14 down to 1.10-68). To our knowledge, this is the first time that several common variants are associated with a rare disease, with very high effect (Osdds-ratio) ranging from 1.58 to 2.55. While two loci displaying association hits had already been shown to influence ECG parameters in the general population, the third one encompasses a transcription factor which had never been related to cardiac arrhythmia. We showed that this factor regulates Nav1.5 channel expression in hearts of homozygous knockout embryos and influence cardiac conduction velocity in adult heterozygous mice. At last, we found that the cumulative effect of the 3 loci on disease susceptibility was unexpectedly large, indicating that common genetic variation may have a strong impact on predisposition to rare disease.

Mutations, Vasculopathy with Fever and Early Onset Strokes

371/3:00 Loss-of-function mutations in CECR1, encoding adenosine deaminase 2, cause systemic vasculopathy with fever and early onset strokes. Q. Zhou, A. Zavialov, M. Boehm, J. Chae, M. Hershfield, R. Sood, S. Burgess, A. Zavialov, D. Chin, C. Toro, R. Lee, M. Quezado, A. Ombrello, D. Stone, I. Aksentijevich, D. Kastner.

Loss-of-Function Mutations in CECR1, Encoding Adenosine Deaminase

2,Cause Systemic Vasculopathy with Fever and Early Onset

Strokes. Q. Zhou1, A. Zavialov2, M. Boehm3, J. Chae1, M. Hershfield4, R.

Sood5, S. Burgess6, A. Zavialov2, D. Chin1, C. Toro7, R. Lee8, M. Quezado9,

A. Ombrello1, D. Stone1, I. Aksentijevich1, D. Kastner1.

1) Inflammatory Disease Section, NHGRI, Bethesda, USA;

2) Turku Centre for Biotechnology, University of Turku, Turku, Finland;

3) Laboratory of Cardiovascular Regenerative Medicine, NHLBI, Bethesda, USA;

4) Department of Medicine, Duke University Medical Center, Durham, USA;

5) Zebrafish Core, NHGRI, Bethesda, USA;

6) Developmental Genomics Section, NHGRI, Bethesda, USA;

7) NIH Undiagnosed Diseases Program, NIH, Bethesda, USA;

8) Translational Surgical Pathology Section, NCI, Bethesda, USA;

9) General Surgical Pathology Section, NCI, Bethesda, USA.

We recently observed 5 unrelated patients with fevers, systemic inflammation, livedo reticularis, vasculopathy, and early-onset recurrent ischemic strokes. We performed exome sequencing on affected patients and their unaffected parents. The 5 patients shared 3 missense mutations in CECR1, encoding adenosine deaminase 2 (ADA2), with the genotypes A109D/ Y453C, Y453C/G47A, G47A/H112Q, R169Q/Y453C, and R169Q/28kb genomic deletion encompassing the 5’UTR and first exon of CECR1.

All mutations are either novel or present at low frequency (<0.001) in several large databases, consistent with the recessive inheritance. The Y453C mutation was present in 2/13004 alleles in an NHLBI database. Both alleles are found in 2 affected siblings who suffered from late-onset ischemic stroke, indicating that heterozygous mutations in ADA2 might be associated with susceptibility to adult stroke. Computer modeling based on the crystal structure of the human ADA2 suggests that CECR1 mutations either disrupt protein stability or impair ADA2 enzyme activity. All patients had at least a 10-fold reduction in serum and plasma concentrations of ADA2, and reduced ADA2-specific adenosine deaminase activity. Western blots showed a decrease in protein expression in supernatants of cultured patients’ cells. ADA2 is homologous to ADA1, which is mutated in some patients with SCID.

In contrast to ADA1, ADA2 is expressed predominantly in myeloid cells and is a secreted protein, and its affinity for adenosine is much less than ADA1. Animal models suggest that ADA2 is the prototype for a family of growth factors (ADGFs).Although there is no mouse homolog of CECR1, there are 2 zebrafish homologs, Cecr1a and Cecr1b. Using morpholino technology to knock down the expression of the ADA2 homologs, we observed intracranial hemorrhages in approximately 50% of the zebrafish embryos harboring the knockdown construct, relative to 3% in controls. Immunohistochemical studies of endothelial cells from patients’ skin biopsies demonstrate a diffuse systemic vasculopathy characterized by impaired endothelial integrity, endothelial cellular activation, and a perivascular infiltrate of CD8 T-cells and CD163-positive macrophages. ADA2 is not expressed in the endothelial cells. Our data suggest that ADA2 may be necessary for vascular integrity in the developing zebrafish as an endothelial cell-extrinsic growth factor, and that the near absence of functional ADA2 in patients may lead to strokes by a similar mechanism.

Genetics of Atherosclerotic Plaque in Patients with Chronic Coronary Artery Disease

372/3:15 Genetic influence on LpPLA2 activity at baseline as evaluated in the exome chip-enriched GWAS study among ~13600 patients with chronic coronary artery disease in the STABILITY (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY) trial. L. Warren, L. Li, D. Fraser, J. Aponte, A. Yeo, R. Davies, C. Macphee, L. Hegg, L. Tarka, C. Held, R. Stewart, L. Wallentin, H. White, M. Nelson, D. Waterworth.

Genetic influence on LpPLA2 activity at baseline as evaluated in the exome chip-enrichedGWASstudy among ~13600 patients with chronic coronary artery disease in the STABILITY (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY) trial.

L. Warren1, L. Li1, D. Fraser1, J. Aponte1, A. Yeo2, R. Davies3, C. Macphee3, L. Hegg3,

L. Tarka3, C. Held4, R. Stewart5, L. Wallentin4, H. White5, M. Nelson1, D.


1) GlaxoSmithKline, Res Triangle Park, NC;

2) GlaxoSmithKline, Stevenage, UK;

3) GlaxoSmithKline, Upper Merion, Pennsylvania, USA;

4) Uppsala Clinical Research Center, Department of Medical Sciences, Uppsala University, Uppsala, Sweden;

5) 5Green Lane Cardiovascular Service, Auckland Cty Hospital, Auckland, New Zealand.

STABILITY is an ongoing phase III cardiovascular outcomes study that compares the effects of darapladib enteric coated (EC) tablets, 160 mg versus placebo, when added to the standard of care, on the incidence of major adverse cardiovascular events (MACE) in subjects with chronic coronary heart disease (CHD). Blood samples for determination of the LpPLA2 activity level in plasma and for extraction of DNA was obtained at randomization. To identify genetic variants that may predict response to darapladib, we genotyped ~900K common and low frequency coding variations using Illumina OmniExpress GWAS plus exome chip in advance of study completion. Among the 15828 Intent-to-Treat recruited subjects, 13674 (86%) provided informed consent for genetic analysis. Our pharmacogenetic (PGx) analysis group is comprised of subjects from 39 countries on five continents, including 10139 Whites of European heritage, 1682 Asians of East Asian or Japanese heritage, 414 Asians of Central/South Asian heritage, 268 Blacks, 1027 Hispanics and 144 others. Here we report association analysis of baseline levels of LpPLA2 to support future PGx analysis of drug response post trial completion. Among the 911375 variants genotyped, 213540 (23%) were rare (MAF < 0.5%).

Our analyses were focused on the drug target, LpPLA2 enzyme activity measured at baseline. GWAS analysis of LpPLA2 activity adjusting for age, gender and top 20 principle component scores identified 58 variants surpassing GWAS-significant threshold (5e-08).

Genome-wide stepwise regression analyses identified multiple independent associations from PLA2G7, CELSR2, APOB, KIF6, and APOE, reflecting the dependency of LpPLA2 on LDL-cholesterol levels. Most notably, several low frequency and rare coding variants in PLA2G7 were identified to be strongly associated with LpPLA2 activity. They are V279F (MAF=1.0%, P= 1.7e-108), a previously known association, and four novel associations due to I1317N (MAF=0.05%, P=4.9e-8), Q287X (MAF=0.05%, P=1.6e-7), T278M (MAF=0.02%, P=7.6e-5) and L389S (MAF=0.04%, P=4.3e-4).

All these variants had enzyme activity lowering effects and each appeared to be specific to certain ethnicity. Our comprehensive PGx analyses of baseline data has already provided great insight into common and rare coding genetic variants associated with drug target and related traits and this knowledge will be invaluable in facilitating future PGx investigation of darapladib response.

Genetics of influence IL-18 regulation in patients with Acute Coronary Syndrome

373/3:30 Genome-wide association study identifies common and rare genetic variants in caspase-1-related genes that influence IL-18 regulation in patients with acute coronary syndrome. A. Johansson, N. Eriksson, E. Hagström, C. Varenhorst, A. Åkerblom, M. Bertilsson, T. Axelsson, B. J. Barratt, R. C. Becker, A. Himmelmann, S. James, H. A. Katus, G. Steg, R. F. Storey, A. Syvänen, L. Wallentin, A. Siegbahn.

Genome-wide association study identifies common and rare genetic

variants in caspase-1-related genes that influence IL-18 regulation in

patients with Acute Coronary Syndrome. A. Johansson1, 2, N. Eriksson1,

E. Hagström1,3, C. Varenhorst1,3, A. Åkerblom1,3, M. Bertilsson1, T. Axelsson4,

B.J. Barratt5, R.C. Becker6, A. Himmelmann7, S. James1,3, H.A.

Katus8, G. Steg9, R.F. Storey10, A. Syvänen4, L. Wallentin1,3, A. Siegbahn1,11.

1) Uppsala Clinical Research Center, Uppsala University, Sweden;

2) Department of Immunoloy, Genetics and Pathology, Uppsala University, Sweden;

3) Department of Medical Sciences, Cardiology, Uppsala University, Sweden;

4) Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Sweden;

5) AstraZeneca R&D, Alderley Park, Cheshire, UK;

6) Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA;

7) AstraZeneca Research and Development, Mölndal, Sweden;

8) Medizinishe Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany;

9) INSERM-Unité 698, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France; Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France;

10) Department of Cardiovascular Science, University of Sheffield, Sheffield, UK;

11) Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sweden.


Interleukin 18 (IL-18) levels are increased in patients with acute coronary syndromes (ACS) and correlated with myocardial injury. We performed a genome-wide association study (GWAS) to identify genetic determinants of IL-18 levels in patients with ACS. In the PLATelet inhibition and patient Outcomes (PLATO) trial, enrolling a broad selection of ACS patients, baseline plasma IL-18 levels were measured in 16633 patients. Of these, 9340 were successfully genotyped using Illumina HumanOmni2.5 or HumanOmniExpressExome BeadChip and SNPs imputed using 1000 Genomes Phase I integrated variant set. Seven independent associations, in five chromosomal regions, were identified. The first region, with two independent (r2 = 0.11) association signals (rs34649619, p = 1.17*10−50 and rs360718, p = 2.03*10−12), is located within IL18. Both top SNPs are located in predicted promoter regions, and the insertion polymorphism rs34649619 (T/TA) disrupts a transcription factor binding site for FOXI1, FOXD3 and FOXA2. The second region, also represented by two independent (r2 = 0.003) association signals (rs385076, p = 6.99*10−72 and rs149451729, p = 3.79*10−16), is located in NLRC4. While rs385076 overlaps with a regulatory region, rs149451729 is a rare coding variant resulting in an amino acid substitution, predicted to be deleterious. The third region is located upstream of CARD16, CARD17, and CARD18 and one of the top SNPs (rs17103763, p = 6.19*10−9) has previously been associated with expression levels of CARD16. The two remaining chromosomal regions are located within GSFMF/MROH6 (rs2290414, p = 5.66*10−17) and RAD17 (rs17229943, p = 5.00*10−12).

While the latter genes have not been associated with IL-18 production previously, others are known to be involved in IL-18 release. NLRC4 is an inflammasome that activates the inflammatory cascade in the presence of bacterial molecules. It recruits and activates procaspase-1, which in its turn is responsible for the maturation of pro-IL-18. CARD16-18, also known as COP1, INCA and ICEBERG, encode caspase inhibitors, known to bind to and prevent procaspase-1 activation. Our results suggest that SNPs in IL18 and caspase-1-associated genes are important for IL-18 production. By combining the identified SNPs in a Mendelian randomization study, the causal effect of IL-18 on clinical endpoints could be further evaluated in a longitudinal study.

Thoracic Aortic Aneurysmal Genes

374/3:45 Prevalence and predictors of pneumothorax in patients with connective tissue disorders enrolled in the GenTAC (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry. J. P. Habashi, G. L. Oswald, K. W. Holmes, E. M. Reynolds, S. LeMaire, W. Ravekes, N. B. McDonnell, C. Maslen, R. V. Shohet, R. E. Pyeritz, R. Devereux, D. M. Milewicz, H. C. Dietz, GenTAC Registry Consortium.

Prevalence and Predictors of Pneumothorax in Patients with Connective Tissue Disorders Enrolled in the GenTAC (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry.

J.P. Habashi1, G.L. Oswald2, K.W. Holmes1,5, E.M.

Reynolds10, S. LeMaire3, W. Ravekes1, N.B. McDonnell4, C. Maslen5, R.V.

Shohet6, R.E. Pyeritz7, R. Devereux8, D.M. Milewicz9, H.C. Dietz2, GenTAC

Registry Consortium.

1) Dept Pediatric Cardiology, Johns Hopkins Univ, Baltimore, MD;

2) Dept. Medical Genetics, Johns Hopkins Univ, Baltimore, MD;

3) Baylor College of Medicine, Houston TX;

4) NIA at Harbor Hospital, Baltimore, MD;

5) Oregon Health & Science University, Portland, OR;

6) Queen’s Medical Center, Honolulu, HI;

7) The University of Pennsylvania, Philadelphia, PA; 8) Weill Cornell Medical College of Cornell University, New York NY;

9) University of Texas Medical School at Houston, Houston, TX;

10) University of Maryland, Baltimore, MD.

Spontaneous pneumothorax—described as escape of air into the pleural space surrounding the lung in the absence of traumatic injury—is a rare occurrence in the general population (0.1-0.5%), however is well recognized in Marfan syndrome (MFS)(4-5%). Associations between pneumothorax and other connective tissue disorders (CTDs) are less well recognized. We sought to examine potential associations of

  • pneumothorax with MFS,
  • vascular Ehlers-Danlos syndrome (vEDS) and other CTDs.


Phenotypic data were analyzed on all GenTAC patients with confirmed diagnoses of

  • MFS,
  • vEDS,
  • Loeys-Dietz syndrome (LDS),
  • bicuspid aortic valve with aortic enlargement (BAVe) or
  • familial thoracic aortic aneurysm and dissection (FTAAD)

to assess the prevalence of pneumothorax and associated features (1918 total pts).

Of 695 patients with Ghent criteria-confirmed MFS, 73 had experienced a spontaneous pneumothorax (prevalence 10.5%), higher than reported in the literature. The frequency of pneumothorax in vEDS patients (16/107, 15%) was similar to the frequency in the MFS group. The prevalences of pneumothorax in LDS (4/73, 5.5%), FTAAD (13/237, 5.5%), and BAVe (19/ 806, 2.4%) were significantly less than that for MFS and vEDS (p<0.001), yet greater than reported for the general population. In MFS patients with a pneumothorax, there was a three-fold increase in reported skeletal features of pectus carinatum, pectus excavatum, scoliosis and/or kyphosis compared to those without pneumothorax. Similarly, in vEDS, there was a four-fold increase in pectus carinatum, scoliosis and kyphosis in those patients with a pneumothorax compared to those without pneumothorax. In a subset of patients with self-reported data (n=846), smoking was not associated with increased prevalence of pneumothorax. Gender was not a predictor of pneumothorax in any of the diagnostic categories analyzed despite literature reports of increased prevalence in males. In patients enrolled in the GenTAC registry with a diagnosis of MFS, vEDS, BAVe, FTAAD or LDS, the prevalence of pneumothorax was significantly increased in all CTDs analyzed as compared to the general population. The prevalence of pneumothorax was significantly higher in patients with MFS or vEDS than in the other CTDs.

These data suggest that skeletal features may be a predictor for pneumothorax. Patients presenting with a spontaneous pneumothorax should be evaluated for several potential CTDs; such an evaluation could unmask an undiagnosed aortic aneurysm.


375/4:00 Surprising clinical lessons from targeted next-generation sequencing of thoracic aortic aneurysmal genes. B. Loeys, D. Proost, G. Vandeweyer, S. Salemink, M. Kempers, G. Oswald, H. Dietz, G. Mortier, L. Van Laer.

Surprising clinical lessons from targeted next generation sequencing of thoracic aortic aneurysmal genes. B. Loeys1,2, D. Proost1, G. Vandeweyer1, S. Salemink2, M. Kempers2, G. Oswald3, H. Dietz3, G. Mortier1, L. Van Laer1.

1) Center for Medical Genetics, University of Antwerp/ Antwerp University Hospital, Antwerp, Belgium;

2) Department of Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;

3) Mc Kusick Nathans Institute for Genetic Medicine, Johns Hopkins University Hospital, Baltimore, USA.

Thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world, is genetically heterogeneous and at least 14 causative genes have been identified, accounting for both syndromic and non-syndromic forms. The diagnosis is not always straightforward because a considerable clinical overlap exists between patients with mutations in different genes, and mutations in the same gene cause a wide phenotypic variability. Molecular confirmation of the diagnosis is becoming increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor-intensive. To shorten the turn-around-time, to increase mutation-uptake and to reduce the overall cost of molecular testing, we developed a TAA gene panel for next generation sequencing (NGS) of 14 TAA genes (ACTA2, COL3A1, EFEMP2, FBN1, FLNA, MYH11, MYLK, NOTCH1, SKI, SLC2A10, SMAD3, TGFB2, TGFBR1 and TGFBR2). We obtained enrichment with Haloplex technology and performed 2×150 bp paired-end runs on a Miseq sequencer in a series of 57 consecutive TAA patients, both syndromic and non-syndromic.

The sensitivity and false positive rate were previously shown to be 100% and 3%, respectively. Applying our NGS approach, we identified a causal mutation in 16 patients (28%). This uptake is really high as on average one molecular study per patient (range 0-6) was performed prior to inclusion in this study. One mutation was found in each of the 6 following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous); two mutations inNOTCH1and eight in FBN1. An additional 6 variants of unknown significance were identified: 2 in FLNA, 2 in NOTCH1, 1 in FBN1 and 1 heterozygous in EFEMP2. All variants were confirmed by Sanger sequencing.

Remarkably, from the eight FBN1 positive patients, three patients had previously been tested FBN1 negative by certified labs, indicating that the sensitivity of Sanger sequencing is not 100%. Interestingly, in two FBN1 mutation positive patients

  • the clinical diagnosis of Marfan syndrome was unsuspected. Similarly,
  • the clinical diagnosis of vascular Ehlers-Danlos syndrome (COL3A1) had not been made. Finally,
  • the ACTA2 mutation was identified postmortem from paraffin-embedded extracted DNA.

We conclude that our NGS approach for TAA genetic testing overcomes the intrinsic hurdles of Sanger sequencing and becomes a powerful tool in the elaboration of clinical phenotypes assigned to different genes.

Read Full Post »

Finding the Genetic Links in Common Disease:  Caveats of Whole Genome Sequencing Studies

Writer and Reporter: Stephen J. Williams, Ph.D.

In the November 23, 2012 issue of Science, Jocelyn Kaiser reports (Genetic Influences On Disease Remain Hidden in News and Analysis)[1] on the difficulties that many genomic studies are encountering correlating genetic variants to high risk of type 2 diabetes and heart disease.  At the recent American Society of Human Genetics annual 2012 meeting, results of several DNA sequencing studies reported difficulties in finding genetic variants and links to high risk type 2 diabetes and heart disease.  These studies were a part of an international effort to determine the multiple genetic events contributing to complex, common diseases like diabetes.  Unlike Mendelian inherited diseases (like ataxia telangiectasia) which are characterized by defects mainly in one gene, finding genetic links to more complex diseases may pose a problem as outlined in the article:

  • Variants may be so rare that massive number of patient’s genome would need to be analyzed
  • For most diseases, individual SNPs (single nucleotide polymorphisms) raise risk modestly
  • Hard to find isolated families (hemophilia) or isolated populations (Ashkenazi Jew)
  • Disease-influencing genes have not been weeded out by natural selection after human population explosion (~5000 years ago) resulted in numerous gene variants
  • What percentage variants account for disease heritability (studies have shown this is as low as 26% for diabetes with the remaining risk determined by environment)

Although many genome-wide-associations studies have found SNPs that have causality to increasing risk diseases such as cancer, diabetes, and heart disease, most individual SNPs for common diseases raise risk by about only 20-40% and would be useless for predicting an individual’s chance they will develop disease and be a candidate for a personalized therapy approach.  Therefore, for common diseases, investigators are relying on direct exome sequencing and whole-genome sequencing to detect these medium-rare risk variants, rather than relying on genome-wide association studies (which are usually fine for detecting the higher frequency variants associated with common diseases).

Three of the many projects (one for heart risk and two for diabetes risk) are highlighted in the article:

1.  National Heart, Lung and Blood Institute Exome Sequencing Project (ESP)[2]: heart, lung, blood

  • Sequenced 6,700 exomes of European or African descent
  • Majority of variants linked to disease too rare (as low as one variant)
  • Groups of variants in the same gene confirmed link between APOC3 and higher risk for early-onset heart attack
  • No other significant gene variants linked with heart disease

2.  T2D-GENES Consortium: diabetes

Sequenced 5,300 exomes of type 2 diabetes patients and controls from five ancestry groups
SNP in PAX4 gene associated with disease in East Asians
No low-frequency variant with large effect though

3.  GoT2D: diabetes

  • After sequencing 2700 patient’s exomes and whole genome no new rare variants above 1.5% frequency with a strong effect on diabetes risk

A nice article by Dr. Sowmiya Moorthie entitled Involvement of rare variants in common disease can be found at the PGH Foundation site http://www.phgfoundation.org/news/5164/ further discusses this conundrum,  and is summarized below:

“Although GWAs have identified many SNPs associated with common disease, they have as yet had little success in identifying the causative genetic variants. Those that have been identified have only a weak effect on disease risk, and therefore only explain a small proportion of the heritable, genetic component of susceptibility to that disease. This has led to the common disease-common variant hypothesis, which predicts that common disease-causing genetic variants exist in all human populations, but each individual variant will necessarily only have a small effect on disease susceptibility (i.e. a low associated relative risk).

An alternative hypothesis is the common disease, many rare variants hypothesis, which postulates that disease is caused by multiple strong-effect variants, each of which is only found in a few individuals. Dickson et al. in a paper in PLoS Biology postulate that these rare variants can be indirectly associated with common variants; they call these synthetic associations and demonstrate how further investigation could help explain findings from GWA studies [Dickson et al. (2010) PLoS Biol. 8(1):e1000294][3].  In simulation experiments, 30% of synthetic associations were caused by the presence of rare causative variants and furthermore, the strength of the association with common variants also increased if the number of rare causative variants increased. “

one_of_many rare variants

Figure from Dr. Moorthie’s article showing the problem of “finding one in many”.

(please   click to enlarge)

Indeed, other examples of such issues concerning gene variant association studies occur with other common diseases such as neurologic diseases and obesity, where it has been difficult to clearly and definitively associate any variant with prediction of risk.

For example, Nuytemans et. al.[4] used exome sequencing to find variants in the vascular protein sorting 3J (VPS35) and eukaryotic transcription initiation factor 4  gamma1 (EIF4G1) genes, tow genes causally linked to Parkinson’s Disease (PD).  Although they identified novel VPS35 variants none of these variants could be correlated to higher risk of PD.   One EIF4G1 variant seemed to be a strong Parkinson’s Disease risk factor however there was “no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development”.

These negative results may have relevance as companies such as 23andme (www.23andme.com) claim to be able to test for Parkinson’s predisposition.  To see a description of the LLRK2 mutational analysis which they use to determine risk for the disease please see the following link: https://www.23andme.com/health/Parkinsons-Disease/. This company and other like it have been subjects of posts on this site (Personalized Medicine: Clinical Aspiration of Microarrays)

However there seems to be more luck with strategies focused on analyzing intronic sequence rather than exome sequence. Jocelyn Kaiser’s Science article notes this in a brief interview with Harry Dietz of Johns Hopkins University where he suspects that “much of the missing heritability lies in gene-gene interactions”.  Oliver Harismendy and Kelly Frazer and colleagues’ recent publication in Genome Biology  http://genomebiology.com/content/11/11/R118 support this notion[5].  The authors used targeted resequencing of two endocannabinoid metabolic enzyme genes (fatty-acid-amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in 147 normal weight and 142 extremely obese patients.

These patients were enrolled in the CRESCENDO trial and patients analyzed were of European descent. However, instead of just exome sequencing, the group resequenced exome AND intronic sequence, especially focusing on promoter regions.   They identified 1,448 single nucleotide variants but using a statistical filter (called RareCover which is referred to as a collapsing method) they found 4 variants in the promoters and intronic areas of the FAAH and MGLL genes which correlated to body mass index.  It should be noted that anandamide, a substrate for FAAH, is elevated in obese patients. The authors did note some issues though mentioning that “some other loci, more weakly or inconsistently associated in the original GWASs, were not replicated in our samples, which is not too surprising given the sample size of our cohort is inadequate to replicate modest associations”.

PLEASE WATCH VIDEO on the National Heart, Lung and Blood Institute Exome Sequencing Project



http://www.phgfoundation.org/news/5164/  PHG Foundation

1.            Kaiser J: Human genetics. Genetic influences on disease remain hidden. Science 2012, 338(6110):1016-1017.

2.            Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G et al: Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 2012, 337(6090):64-69.

3.            Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB: Rare variants create synthetic genome-wide associations. PLoS biology 2010, 8(1):e1000294.

4.            Nuytemans K, Bademci G, Inchausti V, Dressen A, Kinnamon DD, Mehta A, Wang L, Zuchner S, Beecham GW, Martin ER et al: Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease. Neurology 2013, 80(11):982-989.

5.            Harismendy O, Bansal V, Bhatia G, Nakano M, Scott M, Wang X, Dib C, Turlotte E, Sipe JC, Murray SS et al: Population sequencing of two endocannabinoid metabolic genes identifies rare and common regulatory variants associated with extreme obesity and metabolite level. Genome biology 2010, 11(11):R118.

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Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 6/13/2013

with a CASE of  Anti-Ro Antibodies and Reversible Atrioventricular Block

N Engl J Med 2013; 368:2335-2337 June 13, 2013 DOI: 10.1056/NEJMc1300484

As an Introduction to the Genetics of Conduction Disease, we selected the following article which represents the MOST comprehensive review of the Human Cardiac Conduction System presented to date:

Circulation.2011; 123: 904-915 doi: 10.1161/​CIRCULATIONAHA.110.942284

The Cardiac Conduction System

  1. David S. Park, MD, PhD;
  2. Glenn I. Fishman, MD

+Author Affiliations

  1. From the Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY.
  1. Correspondence to Glenn I. Fishman, MD, Leon H. Charney Division of Cardiology, New York University School of Medicine, 522 First Ave, Smilow 801, New York, NY 10016. E-mail glenn.fishman@med.nyu.edu

Key Words:

The human heart beats 2.5 billion times during a normal lifespan, a feat accomplished by cells of the cardiac conduction system (CCS). The functional components of the CCS can be broadly divided into the impulse-generating nodes and the impulse-propagating His-Purkinje system. Human diseases of the conduction system have been identified that alter impulse generation, impulse propagation, or both. CCS dysfunction is primarily due to acquired conditions such as myocardial ischemia/infarct, age-related degeneration, procedural complications, and drug toxicity. Inherited forms of CCS disease are rare, but each new mutation provides invaluable insight into the molecular mechanisms governing CCS development and function. Applying a multidisciplinary approach, which includes human genetic screening, biophysical analysis, and transgenic mouse technology, has yielded a broad array of gene families involved in maintaining normal CCS physiology (Figure 1). In this review, we discuss gene families that have been implicated in human CCS diseases of rhythm, conduction block, accessory conduction, and development (Table). We also investigate evolving therapeutic strategies that may serve as adjuvant or replacement therapy to current implantable pacemakers.

Figure 1.

View larger version:

Figure 1.

Cardiac conduction system cell. Genes identified in human cardiac conduction system disease are highlighted.


Genetic Basis of Conduction System Disease

Diseases of Automaticity

The human sinoatrial node (SAN) is a crescent-shaped, intramural structure with its head located subepicardially at the junction of the right atrium and the superior vena cava and its tail extending 10 to 20 mm along the crista terminalis.26 The SAN has complex 3-dimensional tissue architecture with central and peripheral components made up of distinct ion channel and gap junction expression profiles.27 Central and peripheral cells have different action potential characteristics and conduction properties (Figure 2).27Experimental and computational models have demonstrated that SAN heterogeneity is necessary to maintain normal automaticity and impulse conduction.28,,30

Figure 2.

Figure 2.

Electrophysiological heterogeneity of the sinoatrial node (SAN). The central SAN, the site of dominant pacemaking, is electronically insulated from the hyperpolarizing atrial myocardium through the differential expression of connexins and ion channels. Peripheral SAN cells are electrophysiologically intermediate between central cells and atrial cardiomyocytes. SR indicates sarcoplasmic reticulum.

Pacemaker automaticity is due to spontaneous diastolic depolarization of phase 4, which depolarizes the membrane to threshold potential generating rhythmic action potentials. The current paradigm of SAN automaticity has been modeled as 2 clocks that function in concert, the “membrane voltage clock” and the “calcium clock.” The membrane voltage clock is produced by the net disequilibrium between the decay of outward potassium currents (IK) and the activation of inward currents that include, but are not limited to, background sodium-sensitive current (Ib Na), L- and T-type calcium currents (ICa,L,ICa,T), sustained inward (Ist) current, and hyperpolarization-activated current (If) (Figure 2).27,31,,33

The subsarcolemmal calcium clock contributes to SAN diastolic depolarization through the spontaneous, rhythmic release of Ca2+ from the sarcoplasmic reticulum (SR) via the ryanodine type 2 receptor (RYR2).34 The local intracellular calcium (Cai) elevations drive the sodium-calcium exchange current (INCX) to substitute 1 intracellular Ca2+ for 3 extracellular Na+. The net gain in positive charge results in membrane depolarization.35The elevation of intracellular Ca2+ occurs in the latter third of diastolic depolarization and is sensitive to β-adrenergic stimulation.36

Human mutations affecting the voltage clock

  • (SCN5A and HCN4),

  • calcium clock (RYR2 and CASQ2), or both mechanisms

  • (ANKB) have been identified that negatively affect sinus node function.37,38

Diseases of Conduction BlockConduction block can occur at any level of the CCS and can manifest as sinoatrial exit block, atrioventricular block, infra-Hisian block, or bundle branch block. Impaired conduction can be caused by ion channel defects that alter action potential shape or by defective coupling between cardiomyocytes. Inherited defects in cardiac conduction have been linked to mutations in SCN5A and SCN1B (both affect phase 0) and KCNJ2 (affects phase 3 and 4). 

The cardiac sodium channel consists of the pore-forming α-subunit (encoded by SCN5A) and a modulatory β-subunit (encoded by SCN1B). The α-subunit contains a voltage sensor that allows for rapid activation in response to membrane depolarization. After depolarization, the sodium channel undergoes a period of inactivation, in which it is refractory to further impulses. SCN5A requires membrane repolarization to relieve the inactivated state. The inward rectifier potassium channel, Kir2.1, encoded by KCNJ2, maintains the resting membrane potential. Therefore, proper functioning of Nav1.5 and Kir2.1 is necessary for normal cardiac excitability.


Progressive cardiac conduction defect, or Lev-Lenègre disease, is characterized by age-related, fibrosclerotic degeneration of the His-Purkinje system.6 Impulse propagation through the proximal ventricular conduction system progressively declines, resulting in bundle branch blocks and eventually complete atrioventricular block. An inherited form of Lev-Lenègre disease is associated with loss of function mutations in SCN5A and can exist alone or as overlap syndromes with Brugada or long QT syndrome 3.6 Inherited progressive cardiac conduction defect is associated with a high risk of complete atrioventricular block and Stoke-Adams syncope without ventricular dysrhythmia.7 Schott et al8 identified a mutation in SCN5A that cosegregates with Lenègre disease in a large French family. Affected individuals had variable degrees of conduction block requiring pacemaker implantation in 4 family members because of syncope or complete heart block. Linkage analysis and candidate gene sequencing identified a T>C substitution at position +2 of the donor splice site of intron 22 (IVS22+2 T>C), which results in a mutant lacking the voltage-sensitive segment.8 Functional analysis demonstrated no transient inward sodium current in response to depolarization, consistent with a loss-of-function mutation.6


The majority of patients with Brugada and conduction disease do not have SCN5Amutations. Therefore, modifiers of Nav1.5 expression or function have become the target of candidate gene sequencing approaches. Watanabe et al9 identified SCN1B mutations in 3 families with conduction disease with or without Brugada syndrome. Coexpression of mutant β-subunits with Nav1.5 resulted in diminished sodium current.


Mutations in KCNJ2 have been found in a rare autosomal dominant condition called Andersen-Tawil syndrome, characterized by periodic paralysis, dysmorphic features, polymorphic ventricular tachycardia, and cardiac conduction disease.10,11 ECG evaluation of 96 patients with Andersen-Tawil syndrome from 33 unrelated kindreds revealed conduction defects at multiple levels from the atrioventricular node to the distal conduction system.55 Cardiomyocytes expressing a dominant-negative subunit of Kir2.1 exhibited a 95% reduction in IK1, resulting in significant action potential prolongation. Mouse models of Andersen-Tawil syndrome exhibited a slower heart rate and significant slowing of conduction.56,57

Diseases of Accessory Conduction

Wolff-Parkinson-White (WPW) syndrome is characterized by preexcitation of ventricular myocardium via an accessory pathway (bundle of Kent) that bypasses the normal slow conduction through the atrioventricular node. Ventricular preexcitation is common, with a disease prevalence of 1.5 to 3 per 1000 people.22,58 Histological evaluation of Kent bundles resected from human subjects displayed features of typical ventricular myocytes with expression of connexin 43 (Cx43).59 The expression of high-conductance gap junctions in bypass tracts enables them to preexcite ventricular myocardium, manifesting as a short PR and a slurred QRS complex, or “delta wave,” on the ECG. The vast majority of WPW cases are sporadic, and the underlying mechanism remains unknown; however, rare inherited forms have been reported. Vidaillet et al60 determined that 3.4% of probands with WPW had 1 or more first-degree relatives with accessory conduction.


A familial form of WPW with an autosomal dominant mode of transmission was identified in 2 families. Thirty-one affected individuals had evidence of preexcitation and cardiac hypertrophy. A missense mutation in PRKAG2 was identified that results in a constitutively active form of the γ2 regulatory subunit of AMP-activated protein kinase.22,23 Under normal conditions, AMP-activated protein kinase responds to energy-depleted states by increasing glucose uptake and promoting glycolysis. Transgenic mice expressing a heart-restricted, constitutively active mutant, PRKAG2N488I, recapitulated the human WPW phenotype of cardiac hypertrophy, preexcitation, and conduction defects. The predominant histological finding was ventricular myocyte engorgement with glycogen-laden vacuoles. The disruption of the annulus fibrosus by vacuolated ventricular myocytes resulted in the preexcitation phenotype.61 Using a mouse model of reversible glycogen-storage defect, Wolf et al62 demonstrated that the cardiomyopathy and CCS degeneration seen in PRKAG2N488I mice were reversible processes.


Lalani et al24 reported a novel WPW syndrome associated with microdeletion of the bone morphogenetic protein-2 (Bmp2) region within 20p12.3 that is characterized by variable cognitive deficits and dysmorphic features. The BMPs are members of the transforming growth factor-β superfamily and play a critical role in cardiac development. Mice with cardiac deletion of BMP receptor type Ia (Bmpr1a) were embryonic lethal before E18.5 because of abnormal development of trabecular and compact myocardium, interventricular septum, and endocardial cushion.63 More restricted deletion of Bmpr1a in the atrioventricular canal resulted in defective atrioventricular valve formation and maturation defects in the annulus fibrosus, resulting in preexcitation.64,65


Diseases of CCS Development

Congenital heart disease is the most common form of birth defect, affecting 1% to 2% of live births.66 Arrhythmias may result from defective CCS specification/patterning, malformation or displacement of the conduction system, altered hemodynamics, prolonged hypoxic states, or postoperative sequelae.67,68 Developmentally, the conduction system derives from myocardial precursor cells within the fetal heart.69,,71The process by which conduction cells are specified or recruited into a “conduction” versus “working myocyte” lineage is determined by the regional expression of transcription factors.69,,74 The main transcription factors identified in human CCS development are the T-box and homeobox factors.


Holt-Oram syndrome is an autosomal dominant condition characterized by preaxial radial ray limb deformities (defects of the radius, carpal bones, and/or thumbs) and cardiac septation defects. The septal defects are typically ostium secundum atrial septal defects, muscular ventricular septal defects, and atrioventricular canal defects. Patients with Holt-Oram syndrome manifest variable degrees of CCS dysfunction, such as sinus bradycardia and atrioventricular block, even in the absence of overt structural heart disease. In 1997, Basson et al18 screened 2 families with Holt-Oram syndrome and identified mutations in the T-box transcription factor, TBX5. The T-box transcription factors can function as transcriptional activators or repressors and are known to be critical regulators of cardiac specification and differentiation. Seven TBX family members are expressed in the developing heart, 3 of which (TBX1, TBX5, TBX20) have been linked to human congenital heart disease.75

Mice deficient in Tbx5 were embryonic lethal at E10.5 because of arrested development of the atria and left ventricle. Tbx5+/− mice recapitulated the upper limb and cardiac manifestations of human Holt-Oram syndrome, including the conduction abnormalities.72,76 Significant maturation defects in the atrioventricular canal and ventricular conduction system were present.76 Moskowitz et al76 demonstrated thatTbx5+/− mice have maturation failure of the atrioventricular canal manifesting as persistent atrioventricular rings around the tricuspid and mitral valves. Patterning defects were noted in the His bundle and bundle branches, including complete absence of right bundle branch formation in some cases. Expression of CCS-enriched markers, such as atrial natriuretic factor and Cx40, were found to be significantly downregulated, implicating TBX5 as a transcriptional activator of these genes. TBX5 and the homeobox transcription factor NKX2-5 were found to act synergistically in upregulating atrial natriuretic factor and Cx40 expression.76

Conduction Disease Associated With Neuromuscular Disorders

Neuromuscular disorders represent a diverse collection of diseases that commonly present with cardiac involvement. Mutations have been identified in genes involved in the cytoskeleton, nuclear envelope, and mitochondrial function. Cardiac involvement typically manifests as dilated or hypertrophic cardiomyopathy, atrioventricular conduction defects, and atrial and ventricular dysrhythmias.82


Mutations affecting the nuclear envelope have been associated with significant CCS dysfunction. The inner membrane of the nuclear envelope is a highly organized structure, composed of integral membrane proteins and nuclear cytoskeletal proteins that function together in higher-order chromatin structure and transcriptional regulation. The lamins (A, B, and C) are an integral part of an intermediate filament network that imparts structural rigidity to the inner nuclear membrane. Emerin, a member of the nuclear lamina-associated protein family, putatively mediates anchoring of chromatin to the cytoskeleton. Mutations in emerin (EMD) or lamin A/C (LMNA) result in X-linked Emery-Dreifuss muscular dystrophy and autosomal dominant Emery-Dreifuss muscular dystrophy,20respectively. Individuals with Emery-Dreifuss muscular dystrophy develop progressive skeletal muscle weakness in the first decade of life and cardiac involvement (dilated cardiomyopathy and atrioventricular block) in the second decade.82,83

Arimura et al84 engineered a mouse model of autosomal dominant Emery-Dreifuss muscular dystrophy by knocking-in an Lmna missense mutation (H222P) previously identified from a family with typical autosomal dominant Emery-Dreifuss muscular dystrophy. The mouse model faithfully recapitulated the human disease with LmnaH222P/H222P mice exhibiting locomotive defects, dilated cardiomyopathy, and CCS dysfunction. Telemetric evaluation of the mutant mice revealed PR prolongation and QRS complex widening. A similar CCS defect was seen in mice haploinsufficient in the Lmna gene. Lmna+/− mice exhibited sinus bradycardia with variable degrees of atrioventricular block. Histological evaluation of these mice revealed nuclear deformation and apoptosis in atrioventricular node cells.85 Another engineered mouse line expressing LmnaN195K, known to cause autosomal dominant dilated cardiomyopathy with conduction disease in humans,86 exhibited high-grade atrioventricular block and complete heart block. Biochemical evaluation revealed reduced expression and mislocalization of Cx40 and Cx43 in mutant atrial tissue.87 Desmin staining also revealed structural defects of the sarcomere and intercalated discs.87

Genome-wide expression profiling of Lmna H222P mouse hearts revealed significant increases in mitogen-activated protein kinase (MAPK) signaling pathways.88Hyperactivation of MAPK pathways is associated with cardiomyopathy and CCS dysfunction. A significant increase of the activated forms of 2 MAPKs, JNK and ERK1/2, was noted in mutant hearts that predated the onset of overt or molecularly defined cardiomyopathy.88 Treatment of Lmna H222P mice with an inhibitor of ERK phosphorylation abrogated the increase in biomarkers of cardiomyopathy and restored ejection fraction to normal levels. These findings directly link MAPK hyperactivation to the cardiomyopathic phenotype in Lmna H222P mice.89

On the basis of the phenotypes of these mouse models, lamin A/C appears to maintain the functional integrity of the CCS in 2 ways: (1) protection of the nucleus against mechanical stress and (2) maintenance of proper chromatin organization to ensure accurate gene expression, such as in connexin expression and MAPK signaling pathways.83

Future Directions

Linkage analysis with positional cloning has been a highly effective means of identifying gene mutations within kindreds of monogenic disease. More than 1000 genes have been identified with this approach, including those in this review. With the sequencing of the human genome, the promise of identifying genetic causes of complex, multifactorial diseases is becoming more of a reality. One major step in this direction was the development of genome-wide association studies.94

The genome-wide association study is a test of association between a disease and genetic markers that span the entire genome. The technique relies on the fact that variance at one locus predicts with high probability variance of an adjacent locus because of linkage disequilibrium. In other words, there is nonrandom cosegregation of a series of genetic markers that are close together in the genome. This cluster of linked markers is known as a haplotype. The first study of haplotype structure within 4 populations (Yoruban, Northern/Western Europeans, Chinese, and Japanese) was published in Naturein 2005 by the International HapMap Consortium. Their work reported that individual genetic markers (single nucleotide polymorphisms) predict adjacent markers typically with a resolution of ≈30 000 bp. Considering that the human genome is ≈3×109 bp, they projected that <500 000 single nucleotide polymorphisms would be needed to survey the entire genome for all common genetic variants.94,95

Genome-wide association studies have now been used to identify genetic variants that influence ECG parameters in different populations. Intermediate parameters, such as heart rate or PR interval, were used as surrogate markers of disease for 2 reasons: (1) They have an association with cardiovascular morbidity and atrial fibrillation, and (2) they have tighter associations with gene variants than the actual disease. Holm et al96reported several genome-wide associations using a cutoff P value <1.6×10−9. One locus harboring MYH6 was associated with heart rate, 4 loci (TBX5SCN10ACAV1, andARHGAP24) were associated with PR interval, and 4 loci (TBX5SCN10A6p21, and10q21) were associated with QRS duration. They went on to test these associations with individuals manifesting different arrhythmias in an Icelandic and Norwegian population. Correlations were found between atrial fibrillation and TBX5 and CAV1 (P=4.0×10−5 andP=0.00032, respectively), between advanced atrioventricular block and TBX5 (P=0.0067), and between pacemaker implantation and SCN10A (P=0.0029).

Similar loci were identified by 2 additional independent genome-wide association studies in a European population and an Indian Asian population. Pfeufer et al97 reported 9 loci that were highly associated with PR interval (P<5×10−8) from a meta-analysis of the CHARGE Consortium with >28 000 European subjects. One locus had associations with 2 sodium channels (SCN10A and SCN5A), and 6 loci were near genes involved in cardiac development (CAV1-CAV2NKX2-5SOX5WNT11MEIS1and TBX5-TBX3). Of these,SCN10ASCN5ACAV1-CAV2NKX2-5, and SOX5 were found to be associated with atrial fibrillation. Chambers et al98 also reported the association between SCN10A and PR interval in 6543 Indian Asians. Physiological testing of Scn10a-deficient mice revealed shortened PR intervals in knockout mice with no significant difference in all other ECG and echocardiographic parameters.

The discovery of novel gene families associated with human conduction and arrhythmic diseases with the use of genome-wide association studies is well under way. Identification of SCN10A by 3 independent groups studying different populations confirms the fidelity of this approach. Further experiments confirming the significance of these associations will need to be performed. In addition to identifying novel gene targets, this technique will also aid in the discovery of new associations with noncoding regions in which new epigenetic modifiers and transcriptional/translational regulators, such as microRNAs, will be identified.

Therapeutic Strategies

The current standard of care for symptomatic bradycardia due to conduction system disease is the implantation of an electronic pacemaker. Despite their success, electronic pacemakers have limitations, which include lead complications, finite battery life, potential for infection, lack of autonomic responsiveness, and size restriction in younger patients. These limitations have spurred on the development of biological pacemakers, the premise of which is to restore pacemaking activity with the use of viral-based or stem cell–based gene delivery systems.99 The identification and characterization of genes involved in generating pacemaker currents have allowed biological pacemaker technology to become a reality.

The restoration of sinus pacing rates can be achieved by modulating inward and outward currents to establish or increase the slope of diastolic depolarization in cardiac tissue. Increasing inward currents and/or decreasing outward currents increase the slope of diastolic depolarization and therefore the pacing rate. Genes that have been investigated or are under current investigation include the following: (1) β2-adrenergic receptor,100,101(2) dominant-negative Kir2.1 mutants,102 (3) adenylate cyclase type VI (ACVI),103,104and (4) HCN channels.105 The β2-adrenergic receptor and adenylate cyclase type VI both increase cAMP levels, leading to activation of endogenous HCN channels and calcium clock mechanisms. Although initial animal models using the β2-adrenergic receptor showed promise with transient increases in heart rate, the potential for proarrhythmia and the inability of this approach to establish de novo pacemaker activity limited its efficacy.101

Another approach focused on modifying ionic currents that convert working myocardial cells, which have relatively stable diastolic potentials, into cells with phase 4 diastolic depolarization. It was postulated that atrial and ventricular myocytes have the potential for automaticity, but that hyperpolarizing currents, such as IK1, prevent diastolic depolarization by stabilizing the resting membrane potential. Miake et al102 confirmed this hypothesis when they demonstrated that adenoviral delivery of a dominant-negative Kir2.1 construct into the left ventricle of guinea pigs resulted in conversion of quiescent myocytes into pacemaker cells. Unfortunately, significant action potential prolongation limited the clinical utility of this treatment strategy.102

Rosen and colleagues105,106 demonstrated that automaticity could be induced in quiescent myocardium with the use of heterologous expression of HCN channels that produce the pacemaker current If. Qu and Plotnikov et al demonstrated that stable autonomous rhythms could be generated when adenovirus encoding HCN2 was injected into the left atrium105 or left bundle branch106 of a canine heart. To bypass the limitations of viral-based systems, such as host immune response, several groups reported the successful use of cell-based delivery systems. Plotnikov et al107 reported the successful implantation of human mesenchymal stem cells expressing HCN2 in the left ventricle of a canine model of atrioventricular block. Dogs maintained stable ectopic pacemaker activity for >6 weeks without the use of immunosuppression.107 Human mesenchymal stem cells electronically couple to host myocardium through gap junctions; therefore, conditions with significant gap junction remodeling may affect the efficacy of this method.

Although standalone biological pacemakers may be far into the future, adjuvant biological pacemakers may find real-world utility for current deficiencies of electronic pacemakers, such as limited battery life and device infections. For example, biological preparations used in conjunction with device therapy may be used to extend battery life, decreasing the frequency of generator changes. Transient injectable pacemakers may also function as bridge therapy after lead extraction of an infected device. The need for adjuvant biological pacemakers is clear, but continued refinement of gene- and cell-based delivery systems will be necessary to make this technology a reality.99


Although rare, inherited arrhythmias have become an invaluable tool in identifying the genetic determinants of CCS function. Each new mutation enhances our understanding and appreciation of the biochemical and structural complexity needed for cardiac impulse generation and propagation. This methodology is hampered, however, by the relative scarcity of inherited conditions affecting the CCS. The addition of genome-wide association studies has broadened this search for novel genes beyond rare familial afflictions to include common, multifactorial conditions. It is hoped that this exciting new frontier will bring to light the complex interplay of genes and genetic/epigenetic modifiers that influence the prevalence of common diseases. These genetic screens will ultimately yield a bevy of new gene targets for pharmaceutical or gene-based therapeutics of the future.

Sources of Funding

Studies in the Fishman laboratory are supported by National Institutes of Health grants HL64757, HL081336, and HL82727 and a New York State STEM award (to Dr Fishman) and a Heart Rhythm Foundation Fellowship (to Dr Park).

Genetics of Atrioventricular Conduction Disease in Humans.

Benson DW.


Division of Cardiology, ML7042, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. woody.benson@cchmc.org


Atrioventricular (AV) conduction disease (block) describes impairment of the electrical continuity between the atria and ventricles. Classification of AV block has utilized biophysical characteristics, usually the extent (first, second, or third degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is unknown. In young patients, AV block may result from injury or be the major cardiac manifestation of neuromuscular disease. However, in some cases, AV block has unknown or idiopathic cause. In such cases, familial clustering has been noted and published pedigrees show autosomal dominant inheritance; associated heart disease is common (e.g., congenital heart malformation, cardiomyopathy). The latter finding is not surprising given the common origin of working myocytes and specialized conduction system elements. Using genetic models incorporating reduced penetrance (disease absence in some individuals with disease gene), variable expressivity (individuals with disease gene have different phenotypes), and genetic heterogeneity (similar phenotypes, different genetic cause), molecular genetic causes of AV block are being identified. Mutations identified in genes with diverse functions (transcription, excitability, and energy homeostasis) for the first time provide the means to assess risk and offer insight into the molecular basis of this important clinical condition previously defined only by biophysical characteristics.


Additional Studies on Genetic Congenital AV Block

1) 12738236
Na+ channel mutation leading to loss of function and non-progressive cardiac conduction defects.
BACKGROUND: We previously described a Dutch family in which congenital cardiac conduction disorder has clinically been identified. The ECG of the index patient showed a first-degree AV block associated with extensive ventricular conduction delay. Sequencing of the SCN5A locus coding for the human cardiac Na+ channel revealed a single nucleotide deletion at position 5280, resulting in a frame-shift in the sequence coding for the pore region of domain IV and a premature stop codon at the C-terminus. METHODS AND RESULTS: Wild type and mutant Na+ channel proteins were expressed in Xenopus laevis oocytes and in mammalian cells. Voltage clamp experiments demonstrated the presence of fast activating and inactivating inward currents in cells expressing the wild type channel alone or in combination with the beta1 subinut (SCN1B). In contrast, cells expressing the mutant channels did not show any activation of inward current with or without the beta1 subunit. Culturing transfected cells at 25 degrees C did not restore the Na+ channel activity of the mutant protein. Transient expression of WT and mutant Na+ channels in the form of GFP fusion proteins in COS-7 cells indicated protein expression in the cytosol. But in contrast to WT channels were not associated with the plasma membrane. CONCLUSIONS: The SCN5A/5280delG mutation results in the translation into non-function channel proteins that do not reach the plasma membrane. This could explain the cardiac conduction defects in patients carrying the mutation.
2) 12956334
The genetic origin of atrioventricular conduction disturbance in humans.
Atrioventricular (AV) conduction disturbance (block) describes impairment of the electrical continuity between the atria and ventricles. Clinical classification of AV block has utilized biophysical characteristics, usually the extent (1st, 2nd, 3rd degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is not known. In some casesAV block occurrence is associated with intrauterine exposure to maternal antibody (anti-Ro, anti-La), and other cases are associated with injury (e.g. surgery). Based on familial clustering of idiopathic AV block, a genetic cause has also been suspected. Published pedigrees show autosomal dominant inheritance, and associated heart disease is common (e.g. congenital heart malformation, cardiomyopathy, etc.). The latter finding is not unexpected given the common origin of working myocytes and elements of the specialized conduction system. Using genetic models incorporating reduced penetrance (presence of disease genotype in absence of phenotype), variable expressivity (presence of a disease genotype with variable phenotypes) and genetic heterogeneity (similar phenotypes, different disease genotypes), molecular genetic causes of AV block are being identified. These findings are significant as they provide insight into the molecular basis of a clinical condition previously defined only by biophysical characteristics.
3) 15372490
Genetics of atrioventricular conduction disease in humans.
Atrioventricular (AV) conduction disease (block) describes impairment of the electrical continuity between the atria and ventricles. Classification of AV block has utilized biophysical characteristics, usually the extent (first, second, or third degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is unknown. In young patients, AV block may result from injury or be the major cardiac manifestation of neuromuscular disease. However, in some cases, AV blockhas unknown or idiopathic cause. In such cases, familial clustering has been noted and published pedigrees show autosomal dominant inheritance; associated heart disease is common (e.g., congenital heart malformation, cardiomyopathy). The latter finding is not surprising given the common origin of working myocytes and specialized conduction system elements. Using genetic models incorporating reduced penetrance (disease absence in some individuals with disease gene), variable expressivity (individuals with disease gene have different phenotypes), and genetic heterogeneity (similar phenotypes, different genetic cause), molecular genetic causes of AV block are being identified. Mutations identified in genes with diverse functions (transcription, excitability, and energy homeostasis) for the first time provide the means to assess risk and offer insight into the molecular basis of this important clinical condition previously defined only by biophysical characteristics.


Anti-Ro Antibodies and Reversible Atrioventricular Block

N Engl J Med 2013; 368:2335-2337 June 13, 2013DOI: 10.1056/NEJMc1300484

To the Editor:

Transplacental transfer of anti-Ro antibodies is a well-known cause of conduction defects and permanent atrioventricular block in newborns.1 In adults, conduction disturbances related to these antibodies are rare.2

We report a case of a 26-year-old woman with no history of this condition who was admitted to the hospital through the emergency department after having several syncopal episodes. Electrocardiography (ECG) performed while the patient was at rest showed complete atrioventricular block and ventricular escape rhythm associated with left bundle-branch block (Figure 1AFIGURE 1Electrocardiographic Findings.). Laboratory evaluation included a positive test for antinuclear antibodies (with the HEp-2 cell substrate) at a titer of 1:320, with a speckled pattern and specificity for extractable nuclear antigens, including antibodies against Ro52 confirmed by means of immunoblot and enzyme-linked immunosorbent assays (first measurement of antibodies, 1.2 U per milliliter). No clinical manifestations of rheumatologic disease were present. Other causes of reversible atrioventricular block were ruled out. The patient had no history of cardiac surgery, ablation procedures, or drug use. There was no evidence of infiltrative diseases (e.g., sarcoidosis or amyloidosis) or myocardial ischemia, nor was there clinical suspicion of infectious diseases that cause conduction disturbances (e.g., Lyme disease or Chagas’ disease). Levels of electrolytes and thyrotropin were normal. Transthoracic echocardiography and magnetic resonance imaging were unremarkable.

During the first 4 days after admission, the patient had varying degrees of atrioventricular block. An electrophysiological study showed a mildly prolonged HV interval of 62 msec during sinus rhythm (normal values, 35 to 55 msec) and a pathologic response to atrial pacing, with atrioventricular block occurring after the deflection of the bundle of His during continuous stimulation at a fixed cycle length of 490 msec (Figure 1B). Intravenous methylprednisolone was initiated at a dose of 1 mg per kilogram of body weight per day, and 1:1 atrioventricular conduction was subsequently maintained on surface ECG. A second electrophysiological study during treatment showed normal atrioventricular conduction.

Maintenance immunosuppressive therapy with azathioprine (at a dose of 100 mg daily) and methylprednisolone (at a dose of 4 mg daily) was initiated and continued for 12 months. Serial anti-Ro (SS-A) levels fluctuated during follow-up and became negative after 1 year. Because of the uncertainty of the outcome, a backup pacemaker was implanted. The patient remained completely asymptomatic for 12 months with sustained normal atrioventricular conduction.

In this case of atrioventricular block in an adult patient with positive anti-Ro antibodies, we used electrophysiological testing to localize the conduction defect below the atrioventricular node. This finding, together with left bundle-branch block detected on ECG, suggests specific involvement of the Purkinje fibers. The pathogenesis of cardiac conduction disturbances in adults with positive anti-Ro (SS-A) antibodies remains unclear.3 Experimental studies suggest that anti-Ro antibodies interact with calcium channels and cause reversible inhibition of calcium currents. In fetal hearts, the internalization of these channels leads to apoptosis and fibrosis of the conduction tissue. The presence of a fully developed sarcoplasmic reticulum and the apparent lack of antibody-induced apoptosis in adult cardiomyocytes may explain the differential susceptibility of adult hearts to anti-Ro antibodies2 and, conceivably, the reversibility of the conduction disease in such persons.

Irene Santos-Pardo, M.D.
Melania Martínez-Morillo, M.D.
Roger Villuendas, M.D.
Antoni Bayes-Genis, M.D., Ph.D.
Hospital Universitari Germans Trias i Pujol, Badalona, Spain



Chameides L, Truex RC, Vetter V, Rashkind WJ, Galioto FM Jr, Noonan JA. Association of maternal systemic lupus erythematosus with congenital complete heart block. N Engl J Med 1977;297:1204-1207
Full Text | Web of Science | Medline

Lazzerini PE, Capecchi PL, Laghi-Pasini F. Anti-Ro/SSA antibodies and cardiac arrhythmias in the adult: facts and hypotheses. Scand J Immunol 2010;72:213-222
CrossRef | Web of Science | Medline

Costedoat-Chalumeau N, Georgin-la-Vialle S, Amoura Z, Piette J-C. Anti-SSA/Ro and anti-SSB/La antibody-mediated congenital heart block. Lupus 2005;14:660-664
CrossRef | Web of Science | Medline



New Research on the Genetics of Conduction Disease

Heart failure clinics


conduction diseases (CD) include defects in impulse generation and conduction. Patients with CD may manifest a wide range of clinical presentations, from asymptomatic to potentially life-threatening arrhythmias. The pathophysiologic mechanisms underlying CD are diverse and may have implications for diagnosis, treatment, and prognosis. Known causes of functional CD include cardiac ion channelopathies or defects in modifying proteins, such as cytoskeletal proteins. Progress in molecular biology and genetics along with development of animal models has increased the understanding of the molecular mechanisms of these disorders. This article discusses the genetic basis for CD and its clinical implications.
(Beinart et al. 2010)
Beinart R, Ruskin J, et al. (2010). The genetics of conduction disease. Heart Fail Clin 6 (2): 201-14.
PMID: 20347788  DOI: 10.1016/j.hfc.2009.11.006  PII: S1551-7136(09)00108-1
PLoS genetics


(Curran and Mohler 2012)
Curran J and Mohler PJ (2012). Defining the Pathways Underlying the Prolonged PR Interval in Atrioventricular Conduction Disease. PLoS Genet. 8 (12): e1003154.
PMID: 23236297  DOI: 10.1371/journal.pgen.1003154  PII: PGENETICS-D-12-02668
BMC medical genetics


BACKGROUND: Mutations in the gene encoding the nuclear membrane protein lamin A/C have been associated with at least 7 distinct diseases including autosomal dominant dilated cardiomyopathy withconduction system disease, autosomal dominant and recessive Emery Dreifuss Muscular Dystrophy, limb girdle muscular dystrophy type 1B, autosomal recessive type 2 Charcot Marie Tooth, mandibuloacral dysplasia, familial partial lipodystrophy and Hutchinson-Gilford progeria.METHODS: We used mutation detection to evaluate the lamin A/C gene in a 45 year-old woman with familial dilated cardiomyopathy and conduction system disease whose family has been well characterized for this phenotype 1.RESULTS: DNA from the proband was analyzed, and a novel 2 base-pair deletion c.908_909delCT in LMNA was identified.CONCLUSIONS: Mutations in the gene encoding lamin A/C can lead to significant cardiac conductionsystem disease that can be successfully treated with pacemakers and/or defibrillators. Genetic screening can help assess risk for arrhythmia and need for device implantation.
(MacLeod et al. 2003)
MacLeod HM, Culley MR, et al. (2003). Lamin A/C truncation in dilated cardiomyopathy with conduction disease. BMC Med. Genet. 4: 4.
PMID: 12854972  DOI: 10.1186/1471-2350-4-4
Heart (British Cardiac Society)


(MacRae 2012)
MacRae CA (2012). Pattern recognition: combining informatics and genetics to re-evaluate conduction disease. Heart 98 (17): 1263-4.
PMID: 22875820  DOI: 10.1136/heartjnl-2012-302408  PII: heartjnl-2012-302408
The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology


Atrioventricular (AV) conduction disease (block) describes impairment of the electrical continuity between the atria and ventricles. Classification of AV block has utilized biophysical characteristics, usually the extent (first, second, or third degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is unknown. In young patients, AV block may result from injury or be the major cardiac manifestation of neuromuscular disease. However, in some cases, AV block has unknown or idiopathic cause. In such cases, familial clustering has been noted and published pedigrees show autosomal dominant inheritance; associated heart disease is common (e.g., congenital heart malformation, cardiomyopathy). The latter finding is not surprising given the common origin of working myocytes and specialized conduction system elements. Using genetic models incorporating reduced penetrance (disease absence in some individuals with diseasegene), variable expressivity (individuals with disease gene have different phenotypes), and genetic heterogeneity (similar phenotypes, different genetic cause), molecular genetic causes of AV block are being identified. Mutations identified in genes with diverse functions (transcription, excitability, and energy homeostasis) for the first time provide the means to assess risk and offer insight into the molecular basis of this important clinical condition previously defined only by biophysical characteristics.
(Benson 2004) – ORIGINAL FIRST PAPER on the Subject
Benson DW (2004). Genetics of atrioventricular conduction disease in humans. Anat Rec A Discov Mol Cell Evol Biol 280 (2): 934-9.
PMID: 15372490  DOI: 10.1002/ar.a.20099
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Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

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Reporter: Aviva Lev-Ari, PhD, RN

GWAS Explores Role of Inherited Variants in Childhood ALL

March 20, 2013

NEW YORK (GenomeWeb News) – Inherited genetic variants — including some found at variable frequencies in different human populations — can significantly bump up an individual’s risk of developing acute lymphoblastic leukemia, according to a multi-population genome-wide association study out last night in the Journal of the National Cancer Institute.

“These findings indicate strong associations between inherited genetic variation and ALL susceptibility in children,” senior author Jun Yang, a pharmaceutical sciences researcher with St. Jude Children’s Research Hospital, and colleagues wrote, “and shed new light on ALL molecular etiology in diverse ancestry.”

Through GWAS analyses involving nearly 2,500 children with ALL and almost 11,000 unaffected individuals, Yang and colleagues from St. Jude and elsewhere tracked down ALL-associated loci falling in four genes previously implicated in the disease and in one new chromosome 10 locus.

For those carrying mostly risk versions of the top ALL-associated SNPs in four genes, they found, ALL incidence was far higher than it was in those with no risk alleles or just one risk allele.

Moreover, the team saw examples of risk alleles that occur more often in the Hispanic population than in European or African-American populations — a pattern that study authors said may partly explain the elevated ALL rates described in Hispanic populations in the past.

Previous GWAS support the notion that ALL risk is at least partly inherited, Yang and colleagues explained. But so far variants in just a few genes have been linked to the disease through studies of individuals with European ancestry.

“Although accumulating evidence indicates inherited predisposition to ALL, the genetic basis of ALL susceptibility in diverse ancestry has not been comprehensively examined,” Yang and his co-authors noted.

To begin exploring such questions in individuals from a variety of backgrounds, the group did a GWAS involving cases and controls from diverse ethnic populations, along with analyses focused on individuals with European, African-American, or Hispanic ancestry.

For the discovery stage of the study, the researchers used Affymetrix arrays to genotype 1,605 children from the Children’s Oncology Group study who had been diagnosed with B-cell ALL. Genetic patterns in these patients were compared with those found in 6,661 unaffected control individuals enrolled through the Multi-Ethnic Study of Atherosclerosis.

The analysis uncovered candidate variants that seemed to coincide with ALL risk at one new locus on chromosome 10, along with four loci linked to ALL in the past.

The latter sites are located in and around the ARID5B, IKZF1, CEBPE, and CDKN2A/2B genes, authors of the study explained, while the newly associated locus fell in the vicinity of the BMI1 and PIP4K2A genes.

Following a series of validation studies in another 845 cases and 4,316 controls analyzed by ancestry, the team confirmed that the top SNPs in most of the genes shared ties with ALL regardless of ethnicity. But there was an exception: so far the top SNP in the vicinity of the CEBPE gene seems to have an ALL association that’s specific to Europeans.

In addition, at least some of the ALL-associated variants — particularly those in the ARID5B and PIP4K2A genes — seem to turn up more or less often depending on the population considered.

For instance, the higher risk version of an ALL-linked SNP in PIP4K2A appears to occur with higher-than-usual frequency in the Hispanic population, researchers reported. In contrast, this variant was somewhat less common in the African-American population and intermediate in Europeans.

Such differences may be important, particularly since results of the study suggest that individuals who have inherited predominantly risk alleles at the top SNPs in the ARID5B, IKZF1, CEBPE, and PIP4K2A genes are some nine times more likely to develop ALL than those carrying one or no risk alleles.

“The genetic basis of ALL is most likely to be polygenic,” Yang and colleagues explained. “However, it should be noted that carrying risk variants at merely four SNPs (ARID5B, IKZF1, CEBPE, and PIP4K2A) conferred a nine-fold increase in disease susceptibility.”

Several of these genes, including ARID5B, IKZF1, and CEBPE, have been implicated in processes such as hematopoietic differentiation and development, study authors noted, which are processes that might be expected to be altered in leukemia.

“With these ALL susceptibility genes now on hand (ARID5B, IKZF1, CDKN2A/2B, CEBPE, PIP4K2A), we are armed with novel knowledge of which certain children develop ALL in the first place,” Yang told GenomeWeb Daily News in an email message. “The fact that alterations in these genes lead to ALL raises the question of what would happen if we restore these pathways in ALL and also make them possible exciting therapeutic targets as well.”

Nevertheless, those involved in the study explained that additional work will be needed, both to fine-map causal variants within the ALL-associated regions found already and to uncover additional genetic contributors to ALL risk within and across many different populations.

“The discoveries … are an important step forward in terms of understanding why children develop ALL in the first place, particularly for those with African or Hispanic ethnicity,” Yang said in a statement. “However, this is probably still just a small part of the complete picture.”


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