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Archive for the ‘Biological Networks, Gene Regulation and Evolution’ Category

SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR

Posted in Atherogenic Processes & Pathology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Origins of Cardiovascular Disease, PCSK9 Inhibitor Therapy, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical on January 2, 2014| Leave a Comment »

SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR

Reporter: Aviva Lev-Ari, PhD, RN

Comprehensive Whole-Genome and Candidate Gene Analysis for Response to Statin Therapy in the Treating to New Targets (TNT) Cohort

John F. Thompson, PhD, Craig L. Hyde, PhD, Linda S. Wood, MS, Sara A. Paciga, MA,David A. Hinds, PhD, David R. Cox, MD, PhD, G. Kees Hovingh, MD, PhD and John J.P. Kastelein, MD, PhD

Author Affiliations

From the Helicos BioSciences (J.F.T.), Cambridge, Mass; Molecular Medicine (J.F.T., L.S.W., S.A.P.) and Statistical Applications (C.L.H.), Pfizer Global Research and Development, Groton, Conn; Perlegen Sciences (D.A.H., D.R.C.), Mountain View, Calif; and Department of Vascular Medicine (G.K.H., J.J.P.K.), Academic Medical Center, Amsterdam, The Netherlands.

Correspondence to John J.P. Kastelein, MD, PhD, Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room F4-159.2, 1105 AZ Amsterdam, The Netherlands. E-mail j.j.kastelein@amc.uva.nl or j.s.jansen@amc.uva.nl

Abstract

Background— Statins are effective at lowering low-density lipoprotein cholesterol and reducing risk of cardiovascular disease, but variability in response is not well understood. To address this, 5745 individuals from the Treating to New Targets (TNT) trial were genotyped in a combination of a whole-genome and candidate gene approach to identify associations with response to atorvastatin treatment.

Methods and Results— A total of 291 988 single-nucleotide polymorphisms (SNPs) from 1984 individuals were analyzed for association with statin response, followed by genotyping top hits in 3761 additional individuals. None was significant at the whole-genome level in either the initial or follow-up test sets for association with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglyceride response. In addition to the whole-genome platform, 23 candidate genes previously associated with statin response were analyzed in these 5745 individuals. Three SNPs in apoE were most highly associated with low-density lipoprotein cholesterol response, followed by 1 in PCSK9 with a similar effect size. At the candidate gene level, SNPs in HMGCR were also significant though the effect was less than with those in apoE and PCSK9. rs7412/apoE had the most significant association (P=6×10−30), and its high significance in the whole-genome study (P=4×10−9) confirmed the suitability of this population for detecting effects. Age and gender were found to influence low-density lipoprotein cholesterol response to a similar extent as the most pronounced genetic effects.

Conclusions— Among SNPs tested with an allele frequency of at least 5%, only SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR were also revealed.

SOURCE:

Circulation: Cardiovascular Genetics.2009; 2: 173-181

Published online before print February 12, 2009,

doi: 10.1161/ CIRCGENETICS.108.818062

 

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Statin-Induced Low-Density Lipoprotein Cholesterol Reduction: Genetic Determinants in the Response to Rosuvastatin

Posted in Atherogenic Processes & Pathology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, Technology Transfer: Biotech and Pharmaceutical on January 2, 2014| Leave a Comment »

Statin-Induced Low-Density Lipoprotein Cholesterol Reduction: Genetic Determinants in the Response to Rosuvastatin

Reporter: Aviva Lev-Ari, PhD, RN

Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction

The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial

Daniel I. Chasman, PhD, Franco Giulianini, PhD, Jean MacFadyen, BA, Bryan J. Barratt, PhD, Fredrik Nyberg, MD, PhD, MPH and Paul M Ridker, MD, MPH

Author Affiliations

From the Center for Cardiovascular Disease Prevention (D.I.C., F.G., J.M., P.M.R.), JUPITER Trial Coordinating Center (D.I.C., F.G., J.M., P.M.R.), Brigham and Women’s Hospital and Harvard Medical School (D.I.C., P.M.R.), Boston, MA; Personalised Healthcare and Biomarkers, AstraZeneca Research and Development, Alderley Park, United Kingdom (B.J.B.); AstraZeneca Research and Development, Mölndal, Sweden (F.N.); and Unit of Occupational and Environmental Medicine, Department of Public Health and Community Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (F.N.).

Correspondence to Daniel I. Chasman, PhD, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail dchasman@rics.bwh.harvard.edu

Abstract

Background—In statin trials, each 20 mg/dL reduction in cholesterol results in a 10–15% reduction of annual incidence rates for vascular events. However, interindividual variation in low-density lipoprotein cholesterol (LDL-C) response to statins is wide and may partially be determined on a genetic basis.

Methods and Results—A genome-wide association study of LDL-C response was performed among a total of 6989 men and women of European ancestry who were randomly allocated to either rosuvastatin 20 mg daily or placebo. Single nucleotide polymorphisms (SNPs) for genome-wide association (P<5×10−8) with LDL-C reduction on rosuvastatin were identified at ABCG2, LPA, and APOE, and a further association at PCSK9 was genome-wide significant for baseline LDL-C and locus-wide significant for LDL-C reduction. Median LDL-C reductions on rosuvastatin were 40, 48, 51, 55, 60, and 64 mg/dL, respectively, among those inheriting increasing numbers of LDL-lowering alleles for SNPs at these 4 loci (P trend=6.2×10−20), such that each allele approximately doubled the odds of percent LDL-C reduction greater than the trial median (odds ratio, 1.9; 95% confidence interval, 1.8–2.1;P=5.0×10−41). An intriguing additional association with sub–genome-wide significance (P<1×10-6) was identified for statin related LDL-C reduction at IDOL, which mediates posttranscriptional regulation of the LDL receptor in response to intracellular cholesterol levels. In candidate analysis, SNPs in SLCO1B1 and LDLRwere confirmed as associated with LDL-C lowering, and a significant interaction was observed between SNPs in PCSK9 and LDLR.

Conclusions—Inherited polymorphisms that predominantly relate to statin pharmacokinetics and endocytosis of LDL particles by the LDL receptor are common in the general population and influence individual patient response to statin therapy.

SOURCE

Circulation: Cardiovascular Genetics.2012; 5: 257-264

Published online before print February 13, 2012,

doi: 10.1161/ CIRCGENETICS.111.96114

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Blood Pressure Response to Antihypertensives (atenolol and hydrochlorothiazide): Hypertension Susceptibility Loci Study

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, tagged , , , , on January 2, 2014| Leave a Comment »

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.

Abstract

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.

SOURCE:

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

Published online before print October 19, 2012,

doi: 10.1161/ CIRCGENETICS.112.964080

 

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Personal Genomics for Preventive Cardiology Randomized Trial Design and Challenges

Posted in Biological Networks, Gene Regulation and Evolution, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Proteomics, tagged on January 2, 2014| Leave a Comment »

Personal Genomics for Preventive Cardiology Randomized Trial Design and Challenges

Reporter: Aviva Lev-Ari, PhD, RN

 

Methods in Genetics and Clinical Interpretation Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges

Joshua W. Knowles, MD, PhD, Themistocles L. Assimes, MD, PhD, Michaela Kiernan, PhD, Aleksandra Pavlovic, BS, Benjamin A. Goldstein, PhD, Veronica Yank, MD, Michael V. McConnell, MD, Devin Absher, PhD, Carlos Bustamante, PhD, Euan A. Ashley, MD, DPhil and John P.A. Ioannidis, MD, DSc

Author Affiliations

From the Division of Cardiovascular Medicine (J.W.K., T.L.A., A.P., M.V.M., E.A.A.), Stanford Prevention Research Center (M.K., V.Y., J.P.A.I.), Division of General Medical Disciplines (V.Y.), Department of Genetics (C.B.), Department of Health Research and Policy (J.P.A.I.), Stanford University School of Medicine, Stanford, CA; Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, CA (B.A.G.); HudsonAlpha Institute for Biotechnology, Huntsville, AL (D.A.); Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, CA (J.P.A.I.).

Correspondence to Joshua W. Knowles, MD, PhD, Stanford University School of Medicine, Division of Cardiovascular Medicine, Falk CVRC, 300 Pasteur Dr, Stanford, CA 94305. E-mail knowlej@stanford.edu

Background

Genome-wide association studies (GWAS) have identified more than 1500 disease-associated single nucleotide polymorphisms (SNPs), including many related to atherosclerotic cardiovascular disease (CVD). Associations have been found for most traditional risk factors (TRFs), including

  • lipids,1,2
  • blood pressure/hypertension,3,4
  • weight/body mass index,5,6
  • smoking behavior,7 and
  • diabetes.8–13

GWAS have also identified susceptibility variants for coronary heart disease (CHD). The first and, so far, strongest of these signals was found in the 9p21.3 locus, where common variants in this region increase the relative risk of CVD by 15% to 30% per risk allele in most race/ethnic groups.13–20 Subsequent large-scale GWAS meta-analyses and replication studies in largely white/European populations have led to the reliable identification of an additional 26 loci conferring susceptibility to CHD,2,20–23 all with substantially lower effects sizes compared with the 9p21 locus. Many of these CVD susceptibility loci appear to be conferring risk independent of TRFs and thus cannot currently be assessed by surrogate clinical measures (Table 1). Among the 27 independent loci identified in the most recent large meta-analyses of CVD, 21 were reported not to be associated with any of the TRFs.20,21

 SOURCE

Circulation: Cardiovascular Genetics 2012; 5: 368-376

doi: 10.1161/ CIRCGENETICS.112.962746

 

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Genomics of Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk: Common Genetic Variation in the 3′-BCL11B Gene Desert

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Research, Carotid Artery, Cerebrovascular and Neurodegenerative Diseases, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Origins of Cardiovascular Disease, Peripheral Arterial Disease & Peripheral Vascular Surgery, Personalized and Precision Medicine & Genomic Research, Proteomics, tagged on December 30, 2013| Leave a Comment »

Genomics of Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk: Common Genetic Variation in the 3′-BCL11B Gene Desert

Reporter: Aviva Lev-Ari, PhD, RN

 

Common Genetic Variation in the 3′-BCL11B Gene Desert Is Associated With Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk – The AortaGen Consortium

Gary F. Mitchell, MD*, Germaine C. Verwoert, MSc*, Kirill V. Tarasov, MD, PhD*,Aaron Isaacs, PhD, Albert V. Smith, PhD, Yasmin, BSc, MA, PhD, Ernst R. Rietzschel, MD, PhD, Toshiko Tanaka, PhD, Yongmei Liu, MD, PhD, Afshin Parsa, MD, MPH,Samer S. Najjar, MD, Kevin M. O’Shaughnessy, MA, BM, DPhil, FRCP, Sigurdur Sigurdsson, MSc, Marc L. De Buyzere, MSc, Martin G. Larson, ScD, Mark P.S. Sie, MD, PhD, Jeanette S. Andrews, MS, Wendy S. Post, MD, MS, Francesco U.S. Mattace-Raso, MD, PhD, Carmel M. McEniery, BSc, PhD, Gudny Eiriksdottir, MSc, Patrick Segers, PhD, Ramachandran S. Vasan, MD, Marie Josee E. van Rijn, MD, PhD,Timothy D. Howard, PhD, Patrick F. McArdle, PhD, Abbas Dehghan, MD, PhD,Elizabeth S. Jewell, MS, Stephen J. Newhouse, MSc, PhD, Sofie Bekaert, PhD, Naomi M. Hamburg, MD, Anne B. Newman, MD, MPH, Albert Hofman, MD, PhD, Angelo Scuteri, MD, PhD, Dirk De Bacquer, PhD, Mohammad Arfan Ikram, MD, PhD†, Bruce M. Psaty, MD, PhD†, Christian Fuchsberger, PhD‡, Matthias Olden, PhD‡, Louise V. Wain, PhD§, Paul Elliott, MB, PhD§, Nicholas L. Smith, PhD‖, Janine F. Felix, MD, PhD‖, Jeanette Erdmann, PhD¶, Joseph A. Vita, MD, Kim Sutton-Tyrrell, PhD, Eric J.G. Sijbrands, MD, PhD, Serena Sanna, PhD, Lenore J. Launer, MS, PhD, Tim De Meyer, PhD, Andrew D. Johnson, MD, Anna F.C. Schut, MD, PhD, David M. Herrington, MD, MHS, Fernando Rivadeneira, MD, PhD, Manuela Uda, PhD, Ian B. Wilkinson, MA, BM, FRCP, Thor Aspelund, PhD, Thierry C. Gillebert, MD, PhD, Luc Van Bortel, MD, PhD, Emelia J. Benjamin, MD, MSc, Ben A. Oostra, PhD, Jingzhong Ding, MD, PhD, Quince Gibson, MBA, André G. Uitterlinden, PhD, Gonçalo R. Abecasis, PhD,John R. Cockcroft, BSc, MB, ChB, FRCP, Vilmundur Gudnason, MD, PhD, Guy G. De Backer, MD, PhD, Luigi Ferrucci, MD, Tamara B. Harris, MD, MS, Alan R. Shuldiner, MD, Cornelia M. van Duijn, PhD, Daniel Levy, MD*, Edward G. Lakatta, MD* andJacqueline C.M. Witteman, PhD*

Correspondence to Gary F. Mitchell, MD, Cardiovascular Engineering, Inc, 1 Edgewater Dr, Suite 201A, Norwood, MA 02062. E-mailGaryFMitchell@mindspring.com

↵* These authors contributed equally.

Abstract

Background—Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.

Methods and Results—We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3′-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=−0.075±0.012 SD/allele,P=2.8×10−10; replication β=−0.086±0.020 SD/allele, P=1.4×10−6). Combined results for rs7152623 from 11 cohorts gave β=−0.076±0.010 SD/allele,P=3.1×10−15. The association persisted when adjusted for mean arterial pressure (β=−0.060±0.009 SD/allele, P=1.0×10−11). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=−0.081±0.014 SD/allele, P=2.3×10−9) and older (9 cohorts, n=12 026, β=−0.061±0.014 SD/allele, P=9.4×10−6) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02–1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03–1.16, P=0.004).

Conclusions—Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.

SOURCE:

Circulation: Cardiovascular Genetics.2012; 5: 81-90

Published online before print November 8, 2011,

doi: 10.1161/ CIRCGENETICS.111.959817

 

 

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Abdominal Aortic Aneurysm: Matrix Metalloproteinase-9 Genotype as a Potential Genetic Marker

Posted in Abdominal Aorta, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Medical and Population Genetics, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Proteomics, tagged , , , , on December 30, 2013| Leave a Comment »

Abdominal Aortic Aneurysm: Matrix Metalloproteinase-9 Genotype as a Potential Genetic Marker

Reporter: Aviva Lev-Ari, PhD, RN

 

Matrix Metalloproteinase-9 Genotype as a Potential Genetic Marker for Abdominal Aortic Aneurysm

Tyler Duellman, BS, Christopher L. Warren, PhD, Peggy Peissig, PhD, Martha Wynn, MD and Jay Yang, MD, PhD

Author Affiliations

From the Molecular and Cellular Pharmacology Graduate Program (T.D., J.Y.) and Department of Anesthesiology (M.W., J.Y.), University of Wisconsin School of Medicine and Public Health, Madison; Illumavista Biosciences LLC, Madison, WI (C.L.W.); and Biomedical Informatics Research Center, Marshfield Clinics Research Foundation, Marshfield, WI (P.P.).

Correspondence to Jay Yang, MD, PhD, Department of Anesthesiology, University of Wisconsin SMPH, SMI 301, 1300 University Ave, Madison, WI 53706. E-mailJyang75@wisc.edu

Abstract

Background—Degradation of extracellular matrix support in the large abdominal arteries contribute to abnormal dilation of aorta, leading to abdominal aortic aneurysms, and matrix metalloproteinase-9 (MMP-9) is the predominant enzyme targeting elastin and collagen present in the walls of the abdominal aorta. Previous studies have suggested a potential association between MMP-9 genotype and abdominal aortic aneurysm, but these studies have been limited only to the p-1562 and (CA) dinucleotide repeat microsatellite polymorphisms in the promoter region of the MMP-9 gene. We determined the functional alterations caused by 15 MMP-9 single-nucleotide polymorphisms (SNPs) reported to be relatively abundant in the human genome through Western blots, gelatinase, and promoter–reporter assays and incorporated this information to perform a logistic-regression analysis of MMP-9 SNPs in 336 human abdominal aortic aneurysm cases and controls.

Methods and Results—Significant functional alterations were observed for 6 exon SNPs and 4 promoter SNPs. Genotype analysis of frequency-matched (age, sex, history of hypertension, hypercholesterolemia, and smoking) cases and controls revealed significant genetic heterogeneity exceeding 20% observed for 6 SNPs in our population of mostly white subjects from Northern Wisconsin. A step-wise logistic-regression analysis with 6 functional SNPs, where weakly contributing confounds were eliminated using Akaike information criteria, gave a final 2 SNP (D165N and p-2502) model with an overall odds ratio of 2.45 (95% confidence interval, 1.06–5.70).

Conclusions—The combined approach of direct experimental confirmation of the functional alterations of MMP-9 SNPs and logistic-regression analysis revealed significant association between MMP-9 genotype and abdominal aortic aneurysm.

SOURCE:

Circulation: Cardiovascular Genetics.2012; 5: 529-537

Published online before print August 31, 2012,

doi: 10.1161/ CIRCGENETICS.112.963082

 

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Aortic Aneurysm Pathogenesis: The Role of TGFβRIIb Mutations in Altering Transforming Growth Factor β2 Signal Transduction

Posted in Atherogenic Processes & Pathology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Coagulation Therapy and Internal Bleeding, Frontiers in Cardiology and Cardiovascular Disorders, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Thoracic Aorta, tagged , , , on December 30, 2013| Leave a Comment »

Aortic Aneurysm Pathogenesis: The Role of TGFβRIIb Mutations in  Altering Transforming Growth Factor β2 Signal Transduction

Reporter: Aviva Lev-Ari, PhD, RN

TGFβRIIb Mutations Trigger Aortic Aneurysm Pathogenesis by Altering Transforming Growth Factor β2 Signal Transduction

Katharine J. Bee, PhD, David C. Wilkes, PhD, Richard B. Devereux, MD, Craig T. Basson, MD, PhD and Cathy J. Hatcher, PhD

Author Affiliations

From the Center for Molecular Cardiology, Greenberg Division of Cardiology, Weill Cornell Medical College, New York, NY.

Correspondence to Cathy J. Hatcher, PhD, Greenberg Division of Cardiology, Weill Cornell Medical College, 525 E. 68th St, New York, NY 10065. E-mailcjhatche@med.cornell.edu

Abstract

Background—Thoracic aortic aneurysm (TAA) is a common progressive disorder involving gradual dilation of the ascending and/or descending thoracic aorta that eventually leads to dissection or rupture. Nonsydromic TAA can occur as a genetically triggered, familial disorder that is usually transmitted in a monogenic autosomal dominant fashion and is known as familial TAA. Genetic analyses of families affected with TAA have identified several chromosomal loci, and further mapping of familial TAA genes has highlighted disease-causing mutations in at least 4 genes: myosin heavy chain 11 (MYH11), α-smooth muscle actin (ACTA2), and transforming growth factor β receptors I and II (TGFβRI and TGFβRII).

Methods and Results—We evaluated 100 probands to determine the mutation frequency in MYH11, ACTA2, TGFβRI, and TGFβRII in an unbiased population of individuals with genetically mediated TAA. In this study, 9% of patients had a mutation in one of the genes analyzed, 3% of patients had mutations in ACTA2, 3% in MYH11, 1% in TGFβRII, and no mutations were found in TGFβRI. Additionally, we identified mutations in a 75 base pair alternatively spliced TGFβRII exon, exon 1a that produces the TGFβRIIb isoform and accounted for 2% of patients with mutations. Our in vitro analyses indicate that the TGFβRIIb activating mutations alter receptor function on TGFβ2 signaling.

Conclusions—We propose that TGFβRIIb expression is a regulatory mechanism for TGFβ2 signal transduction. Dysregulation of the TGFβ2 signaling pathway, as a consequence of TGFβRIIb mutations, results in aortic aneurysm pathogenesis.

SOURCE: 

Circulation: Cardiovascular Genetics.2012; 5: 621-629

Published online before print October 24, 2012,doi: 10.1161/ CIRCGENETICS.112.964064

 

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The Role of Sibling Kinship, Sex, and Age of Ischemic Stroke Onset: The Familial Component

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Genetics, Coagulation Therapy and Internal Bleeding, Population Health Management, Genetics & Pharmaceutical, Statistical Methods for Research Evaluation, tagged , , , on December 30, 2013| Leave a Comment »

The Role of Sibling Kinship, Sex, and Age of Ischemic Stroke Onset: The Familial Component

Reporter: Aviva Lev-Ari, PhD, RN

 

Familial Effects on Ischemic Stroke – The Role of Sibling Kinship, Sex, and Age of Onset

Katherine Kasiman, MSc, Cecilia Lundholm, MSc, Sven Sandin, MSc, Ninoa Malki, MSc, Pär Sparén, PhD and Erik Ingelsson, MD, PhD

Author Affiliations

From the Department of Medical Epidemiology and Biostatistics (K.K., C.L., S.S., N.M., P.S., E.I.), Karolinska Institutet, Stockholm, Sweden; Centre for Molecular Epidemiology (K.K.), Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

Correspondence to Prof Erik Ingelsson, MD, PhD, FAHA, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Nobels väg 12A, SE-171 77 Stockholm, Sweden. E-mail erik.ingelsson@ki.se

Abstract

Background—Previous studies on familial risk of ischemic stroke have supported genetic influence on the disease incidence. This study aimed to characterize these familial effects in a nationwide population-based study by taking into account sibling relations, sex of siblings, and age of onset, with respect to ischemic stroke incidence.

Methods and Results—Incident ischemic stroke cases identified from the Swedish Hospital Discharge and Cause of Death Registers between 1987 and 2007 were linked to their stroke-free siblings (study participants), forming an exposed sib-pair. Each exposed sib-pair was matched up to 5 unexposed sib-pairs from the Multi-Generation Registry by birth and calendar years. Incident ischemic stroke risk was assessed using hazard estimates obtained from stratified Cox regression analyses. A total of 30 735 exposed and 152 391 unexposed study participants were included in the analyses. The overall risk of incident ischemic stroke when exposed was significantly increased (relative risk, 1.61; 95% confidence interval, 1.48–1.75;P<0.001). Familial risk was higher in full (relative risk, 1.64; 95% confidence interval, 1.50–1.81; P<0.001) than in half (relative risk, 1.41; 95% confidence interval, 1.10–1.82; P=0.007) siblings. Familial risk of early ischemic stroke almost doubled when exposed to early ischemic stroke (relative risk, 1.94; 95% confidence interval, 1.41–2.67; P<0.001).

Conclusions—There was a 60% increased risk for ischemic stroke in individuals having a sibling with prior stroke. The familial effect was even higher for full-sibling relations. Familial effects were observed in both male and female individuals, and no differential effects depending on the sex of either of the siblings were found.

Published online before print March 8, 2012,

doi: 10.1161/ CIRCGENETICS.111.962191

http://circgenetics.ahajournals.org/content/5/2/226.abstract?sid=5201ab39-7f11-4007-b159-2d1e15663cd5

 

 

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Strong Lipid Gene Contribution But No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits: Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals

Posted in Atherogenic Processes & Pathology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research on December 30, 2013| Leave a Comment »

Strong Lipid Gene Contribution But No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits: Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals

Reporter: Aviva Lev-Ari, PhD, RN

Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution But No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits

Kati Kristiansson, PhD, Markus Perola, MD, PhD, Emmi Tikkanen, MSc, Johannes Kettunen, PhD, Ida Surakka, MSc, Aki S. Havulinna, DSc (Tech.), Alena Stančáková, MD, PhD, Chris Barnes, PhD, Elisabeth Widen, MD, PhD, Eero Kajantie, MD, PhD,Johan G. Eriksson, MD, DMSc, Jorma Viikari, MD, PhD, Mika Kähönen, MD, PhD,Terho Lehtimäki, MD, PhD, Olli T. Raitakari, MD, PhD, Anna-Liisa Hartikainen, MD, PhD, Aimo Ruokonen, MD, PhD, Anneli Pouta, MD, PhD, Antti Jula, MD, PhD, Antti J. Kangas, MSc, Pasi Soininen, PhD, Mika Ala-Korpela, PhD, Satu Männistö, PhD, Pekka Jousilahti, MD, PhD, Lori L. Bonnycastle, PhD, Marjo-Riitta Järvelin, MD, PhD,Johanna Kuusisto, MD, PhD, Francis S. Collins, MD, PhD, Markku Laakso, MD, PhD,Matthew E. Hurles, PhD, Aarno Palotie, MD, PhD, Leena Peltonen, MD, PhD*, Samuli Ripatti, PhD and Veikko Salomaa, MD, PhD

Correspondence to Dr Kati Kristiansson, National Institute for Health and Welfare, University of Helsinki, Biomedicum, PL 104, FI-00251 Helsinki, Finland. E-mailkati.kristiansson@thl.fi

Abstract

Background—Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in 4 Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and nuclear magnetic resonance-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis, and built a genetic risk score for MetS.

Methods and Results—A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all 4 study samples (P=7.23×10−9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 was associated with various very low density lipoprotein, triglyceride, and high-density lipoprotein metabolites (P=0.024–1.88×10−5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these were associated with lipid phenotypes, and none with 2 or more uncorrelated MetS components. A genetic risk score, calculated as the number of risk alleles in loci associated with individual MetS traits, was strongly associated with MetS status.

Conclusions—Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits, such as hypertension and glucose intolerance.

 SOURCE:

Circulation: Cardiovascular Genetics.2012; 5: 242-249

Published online before print March 7, 2012,

doi: 10.1161/ CIRCGENETICS.111.961482

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Resuscitation From Sudden Cardiac Arrest: Common Variation in Fatty Acid Genes

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Proteomics, tagged , , , on December 18, 2013| Leave a Comment »

Resuscitation From Sudden Cardiac Arrest: Common Variation in Fatty Acid Genes

Reporter: Aviva Lev-Ari, PhD, RN

Common Variation in Fatty Acid Genes and Resuscitation From Sudden Cardiac Arrest

Catherine O. Johnson, PhD, MPH, Rozenn N. Lemaitre, PhD, MPH, Carol E. Fahrenbruch, MSPH, Stephanie Hesselson, PhD, Nona Sotoodehnia, MD, MPH,Barbara McKnight, PhD, Kenneth M. Rice, PhD, Pui-Yan Kwok, MD, PhD, David S. Siscovick, MD, MPH and Thomas D. Rea, MD, MPH

Author Affiliations

From the Departments of Medicine (C.O.J., R.N.L., N.S., D.S.S., T.D.R.), Biostatistics (B.M., K.M.R.), and Epidemiology (D.S.S), University of Washington, Seattle; King County Emergency Medical Services, Seattle, WA (C.E.F.); and Institute of Human Genetics, University of California San Francisco (S.H., P.-Y.K.).

Correspondence to Catherine O. Johnson, PhD, MPH, Department of Medicine, University of Washington, CHRU 1730 Minor Ave, Suite 1360, Seattle, WA 98101. E-mail johnsoco@uw.edu

Abstract

Background—Fatty acids provide energy and structural substrates for the heart and brain and may influence resuscitation from sudden cardiac arrest (SCA). We investigated whether genetic variation in fatty acid metabolism pathways was associated with SCA survival.

Methods and Results—Subjects (mean age, 67 years; 80% male, white) were out-of-hospital SCA patients found in ventricular fibrillation in King County, WA. We compared subjects who survived to hospital admission (n=664) with those who did not (n=689), and subjects who survived to hospital discharge (n=334) with those who did not (n=1019). Associations between survival and genetic variants were assessed using logistic regression adjusting for age, sex, location, time to arrival of paramedics, whether the event was witnessed, and receipt of bystander cardiopulmonary resuscitation. Within-gene permutation tests were used to correct for multiple comparisons. Variants in 5 genes were significantly associated with SCA survival. After correction for multiple comparisons, single-nucleotide polymorphisms in ACSL1 and ACSL3 were significantly associated with survival to hospital admission. Single-nucleotide polymorphisms in ACSL3, AGPAT3, MLYCD, and SLC27A6 were significantly associated with survival to hospital discharge.

Conclusions—Our findings indicate that variants in genes important in fatty acid metabolism are associated with SCA survival in this population.

SOURCE:

Circulation: Cardiovascular Genetics.2012; 5: 422-429

Published online before print June 1, 2012

doi: 10.1161/ CIRCGENETICS.111.961912

 

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