Archive for January 2nd, 2014

Response to Rosuvastatin in Patients With Acute Myocardial Infarction: Hepatic Metabolism and Transporter Gene Variants Effect

Reporter: Aviva Lev-Ari, PhD, RN


Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

The GEOSTAT-1 Study

Kristian M. Bailey, MBChB, Simon P.R. Romaine, BSc, Beryl M. Jackson, RGN, Amanda J. Farrin, MSc, Maria Efthymiou, MSc, Julian H. Barth, MD, Joanne Copeland, BSc,Terry McCormack, MBBS, Andrew Whitehead, MSc, Marcus D. Flather, MBBS, Nilesh J. Samani, MD, FMedSci, Jane Nixon, PhD, Alistair S. Hall, MD, PhD, Anthony J. Balmforth, PhD and on behalf of the SPACE ROCKET Trial Group

Author Affiliations

From the Division of Cardiovascular and Diabetes Research (K.M.B., S.P.R.R., B.M.J., A.J.B.), and Division of Cardiovascular and Neuronal Remodelling (A.S.H.), Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom; Clinical Trials Research Unit (A.J.F., M.E., J.C., J.N.), University of Leeds, Leeds, United Kingdom; Clinical Biochemistry (J.H.B.), Leeds General Infirmary, Leeds, United Kingdom; Whitby Group Practice (T.M.), Spring Vale Medical Centre, Whitby, North Yorkshire, United Kingdom; Pharmacy Department (A.W.), Leeds General Infirmary, Leeds, United Kingdom; Clinical Trials and Evaluation Unit (M.D.F.), Royal Brompton and Harefield NHS Trust and Imperial College, London, United Kingdom; and Department of Cardiovascular Sciences (N.J.S.), University of Leicester, Leicester, United Kingdom.

Correspondence to Alistair S. Hall, Clinical Cardiology, Multidisciplinary Cardiovascular Research Centre (MCRC), G Floor, Jubilee Building, Leeds General Infirmary, Leeds, LS1 3EX, United Kingdom. E-mail A.S.Hall@leeds.ac.uk

* Dr Bailey, Mr Romaine, Dr Hall, and Dr Balmforth contributed equally to this study.


Background— Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy.

Methods and Results— The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415).

Conclusion— The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg.

Clinical Trial Registration— URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.


Circulation: Cardiovascular Genetics.2010; 3: 276-285

Published online before print March 5, 2010,

doi: 10.1161/ CIRCGENETICS.109.898502

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Voltage-Gated Calcium Channel and Pharmacogenetic Association with Adverse Cardiovascular Outcomes: Hypertension Treatment with Verapamil SR (CCB) vs Atenolol (BB) or Trandolapril (ACE)

Reporter: Aviva Lev-Ari, PhD, RN

Genetic Variation in the β2 Subunit of the Voltage-Gated Calcium Channel and Pharmacogenetic Association With Adverse Cardiovascular Outcomes in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES)

Yuxin Niu, PhD*Yan Gong, PhD*Taimour Y. Langaee, PhD, Heather M. Davis, PharmD, Hazem Elewa, PhD, Amber L. Beitelshees, PharmD, MPH, James I. Moss, PhD, Rhonda M. Cooper-DeHoff, PharmD, Carl J. Pepine, MD and Julie A. Johnson, PharmD

Author Affiliations

From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.N., Y.G., T.Y.L., H.M.D., H.E., J.I.M., R.M.C.-D., J.A.J.), College of Pharmacy, University of Florida, Gainesville, Fla; Division of Endocrinology, Diabetes and Nutrition (A.L.B.), University of Maryland School of Medicine, Baltimore, Md; and Division of Cardiovascular Medicine (R.M.C.-D., C.J.P., J.A.J.), University of Florida College of Medicine, Gainesville, Fla.

Correspondence to Julie A. Johnson, PharmD, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, PO Box 100486, Gainesville, FL 32610. E-mail Johnson@cop.ufl.edu

* Drs Niu and Gong contributed equally to this work.


Background— Single-nucleotide polymorphisms (SNPs) within the regulatory β2 subunit of the voltage-gated calcium channel (CACNB2) may contribute to variable treatment response to antihypertensive drugs and adverse cardiovascular outcomes.

Methods and Results— SNPs in CACNB2 from 60 ethnically diverse individuals were identified and characterized. Three common SNPs (rs2357928, rs7069292, and rs61839258) and a genome-wide association study-identified intronic SNP (rs11014166) were genotyped for a clinical association study in 5598 hypertensive patients with coronary artery disease randomized to a β-blocker (BB) or a calcium channel blocker (CCB) treatment strategy in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES). Reporter gene assays were conducted on the promoter SNP, showing association with clinical outcomes. Twenty-one novel SNPs were identified. A promoter A>G SNP (rs2357928) was found to have significant interaction with treatment strategy for adverse cardiovascular outcomes (P for interaction, 0.002). In whites, rs2357928 GG patients randomized to CCB were more likely to experience an adverse outcome than those randomized to BB treatment strategy, with adjusted hazard ratio (HR) (CCB versus BB) of 2.35 (95% CI, 1.19 to 4.66; P=0.014). There was no evidence for such treatment difference in AG (HR, 1.16; 95% CI, 0.75 to 1.79; P=0.69) and AA (HR, 0.63; 95% CI, 0.36 to 1.11; P=0.11) patients. This finding was consistent in Hispanics and blacks. CACNB2 rs11014166 showed similar pharmacogenetic effect in Hispanics, but not in whites or blacks. Reporter assay analysis of rs2357928 showed a significant increase in promoter activity for the G allele compared to the A allele.

Conclusions— These data suggest that genetic variation within CACNB2 may influence treatment-related outcomes in high-risk patients with hypertension.

Our association study suggests significant pharmacogenetic effects for the promoter SNP rs2357928 in CACNB2 such that for minor allele homozygotes, a verapamil SR-based CCB treatment strategy is associated with substantially higher risk for adverse cardiovascular outcome compared with an atenolol-based BB treatment strategy. These findings were validated in a second ethnic group and further supported by in vitro studies suggesting differential transcriptional activity with this promoter SNP. Additional studies in other cohorts are required, but these data suggest that this CACNB2 SNP may have future potential for guiding selection of antihypertensive drug therapy among patients with CAD.

Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier:NCT00133692.


Circulation: Cardiovascular Genetics.2010; 3: 548-555


doi: 10.1161/ CIRCGENETICS.110.957654

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Curation, HealthCare System in the US, and Calcium Signaling Effects on Cardiac Contraction, Heart Failure, and Atrial Fibrillation, and the Relationship of Calcium Release at the Myoneural Junction to Beta Adrenergic Release

Curation, HealthCare System in the US, and Calcium Signaling Effects on Cardiac Contraction, Heart Failure, and Atrial Fibrillation, and the Relationship of Calcium Release at the Myoneural Junction to Beta Adrenergic Release

Curator and e-book Contributor: Larry H. Bernstein, MD, FCAP
Curator and BioMedicine e-Series Editor-in-Chief: Aviva Lev Ari, PhD, RN


Content Consultant to Six-Volume e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC

This portion summarises what we have covered and is now familiar to the reader.  There are three related topics, and an extension of this embraces other volumes and chapters before and after this reading.  This approach to the document has advantages over the multiple authored textbooks that are and have been pervasive as a result of the traditional publication technology.  It has been stated by the founder of ScoopIt, that amount of time involved is considerably less than required for the original publications used, but the organization and construction is a separate creative process.  In these curations we amassed on average five articles in one curation, to which, two or three curators contributed their views.  There were surprises, and there were unfulfilled answers along the way.  The greatest problem that is being envisioned is the building a vision that bridges and unmasks the hidden “dark matter” between the now declared “OMICS”, to get a more real perspective on what is conjecture and what is actionable.  This is in some respects unavoidable because the genome is an alphabet that is matched to the mino acid sequences of proteins, which themselves are three dimensional drivers of sequences of metabolic reactions that can be altered by the accumulation of substrates in critical placements, and in addition, the proteome has functional proteins whose activity is a regulatory function and not easily identified.  In the end, we have to have a practical conception, recognizing the breadth of evolutionary change, and make sense of what we have, while searching for more.

We introduced the content as follows:

1. We introduce the concept of curation in the digital context, and it’s application to medicine and related scientific discovery.

Topics were chosen were used to illustrate this process in the form of a pattern, which is mostly curation, but is significantly creative, as it emerges in the context of this e-book.

  • Alternative solutions in Treatment of Heart Failure (HF), medical devices, biomarkers and agent efficacy is handled all in one chapter.
  • PCI for valves vs Open heart Valve replacement
  • PDA and Complications of Surgery — only curation could create the picture of this unique combination of debate, as exemplified of Endarterectomy (CEA) vs Stenting the Carotid Artery (CAS), ischemic leg, renal artery stenosis.

2. The etiology, or causes, of cardiovascular diseases consist of mechanistic explanations for dysfunction relating to the heart or vascular system. Every one of a long list of abnormalities has a path that explains the deviation from normal. With the completion of the analysis of the human genome, in principle all of the genetic basis for function and dysfunction are delineated. While all genes are identified, and the genes code for all the gene products that constitute body functions, there remains more unknown than known.

3. Human genome, and in combination with improved imaging methods, genomics offers great promise in changing the course of disease and aging.

4. If we tie together Part 1 and Part 2, there is ample room for considering clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go.


Curation is an active filtering of the web’s  and peer reviewed literature found by such means – immense amount of relevant and irrelevant content. As a result content may be disruptive. However, in doing good curation, one does more than simply assign value by presentation of creative work in any category. Great curators comment and share experience across content, authors and themes.
Great curators may see patterns others don’t, or may challenge or debate complex and apparently conflicting points of view.  Answers to specifically focused questions comes from the hard work of many in laboratory settings creatively establishing answers to definitive questions, each a part of the larger knowledge-base of reference. There are those rare “Einstein’s” who imagine a whole universe, unlike the three blindmen of the Sufi tale.  One held the tail, the other the trunk, the other the ear, and they all said this is an elephant!
In my reading, I learn that the optimal ratio of curation to creation may be as high as 90% curation to 10% creation. Creating content is expensive. Curation, by comparison, is much less expensive.  The same source says “Scoop.it is my content marketing testing “sandbox”. In sharing, he says that comments provide the framework for what and how content is shared.

Healthcare and Affordable Care Act

We enter year 2014 with the Affordable Care Act off to a slow start because of the implementation of the internet signup requiring a major repair, which is, unfortunately, as expected for such as complex job across the US, and with many states unwilling to participate.  But several states – California, Connecticut, and Kentucky – had very effective state designed signups, separate from the federal system.  There has been a very large rush and an extension to sign up. There are many features that we can take note of:

1. The healthcare system needed changes because we have the most costly system, are endowed with advanced technology, and we have inexcusable outcomes in several domains of care, including, infant mortality, and prenatal care – but not in cardiology.

2. These changes that are notable are:

  • The disparities in outcome are magnified by a large disparity in highest to lowest income bracket.
  • This is also reflected in educational status, and which plays out in childhood school lunches, and is also affected by larger class size and cutbacks in school programs.
  • This is not  helped by a large paralysis in the two party political system and the three legs of government unable to deal with work and distraction.
  • Unemployment is high, and the banking and home construction, home buying, and rental are in realignment, but interest rates are problematic.

3.  The  medical care system is affected by the issues above, but the complexity is not to be discounted.

  •  The medical schools are unable at this time to provide the influx of new physicians needed, so we depend on a major influx of physicians from other countries
  • The technology for laboratories, proteomic and genomic as well as applied medical research is rejuvenating the practice in cardiology more rapidly than any other field.
  • In fields that are imaging related the life cycle of instruments is shorter than the actual lifetime use of the instruments, which introduces a shortening of ROI.
  • Hospitals are consolidating into large consortia in order to maintain a more viable system for referral of specialty cases, and also is centralizing all terms of business related to billing.
  • There is reduction in independent physician practices that are being incorporated into the hospital enterprise with Part B billing under the Physician Organization – as in Partners in Greater Boston, with the exception of “concierge” medical practices.
  • There is consolidation of specialty laboratory services within state, with only the most specialized testing going out of state (Quest, LabCorp, etc.)
  • Medicaid is expanded substantially under the new ACA.
  • The federal government as provider of services is reducing the number of contractors for – medical devices, diabetes self-testing, etc.
  • The current rearrangements seeks to provide a balance between capital expenses and fixed labor costs that it can control, reduce variable costs (reagents, pharmaceutical), and to take in more patients with less delay and better performance – defined by outside agencies.

Cardiology, Genomics, and calcium ion signaling and ion-channels in cardiomyocyte function in health and disease – including heart failure, rhythm abnormalities, and the myoneural release of neurotransmitter at the vesicle junction.

This portion is outlined as follows:

2.1 Human Genome: Congenital Etiological Sources of Cardiovascular Disease

2.2 The Role of Calcium in Health and Disease

2.3 Vasculature and Myocardium: Diagnosing the Conditions of Disease

Genomics & Genetics of Cardiovascular Disease Diagnoses

actin cytoskeleton

wall stress, ventricular workload, contractile reserve

Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

calcium and actin skeleton, signaling, cell motility

hypertension & vascular compliance

Genetics of Conduction Disease

Ca+ stimulated exostosis: calmodulin & PKC (neurotransmitter)

complications & MVR

disruption of Ca2+ homeostasis cardiac & vascular smooth muscle

synaptotagmin as Ca2+ sensor & vesicles

atherosclerosis & ion channels

It is increasingly clear that there are mutations that underlie many human diseases, and this is true of the cardiovascular system.  The mutations are mistakes in the insertion of a purine nucleotide, which may or may not have any consequence.  This is why the associations that are being discovered in research require careful validation, and even require demonstration in “models” before pursuing the design of pharmacological “target therapy”.  The genomics in cardiovascular disease involves very serious congenital disorders that are asserted early in life, but the effects of and development of atherosclerosis involving large and medium size arteries has a slow progression and is not dominated by genomic expression.  This is characterized by loss of arterial elasticity. In addition there is the development of heart failure, which involves the cardiomyocyte specifically.  The emergence of regenerative medical interventions, based on pleuripotent inducible stem cell therapy is developing rapidly as an intervention in this sector.

Finally, it is incumbent on me to call attention to the huge contribution that research on calcium (Ca2+) signaling has made toward the understanding of cardiac contraction and to the maintenance of the heart rhythm.  The heart is a syncytium, different than skeletal and smooth muscle, and the innervation is by the vagus nerve, which has terminal endings at vesicles which discharge at the myocyte junction.  The heart specifically has calmodulin kinase CaMK II, and it has been established that calmodulin is involved in the calcium spark that triggers contraction.  That is only part of the story.  Ion transport occurs into or out of the cell, the latter termed exostosis.  Exostosis involves CaMK II and pyruvate kinase (PKC), and they have independent roles.  This also involves K+-Na+-ATPase.  The cytoskeleton is also discussed, but the role of aquaporin in water transport appears elsewhere, as the transport of water between cells.  When we consider the Gibbs-Donnan equilibrium, which precedes the current work by a century, we recall that there is an essential balance between extracellular Na+ + Ca2+ and the intracellular K+ + Mg2+, and this has been superceded by an incompletely defined relationship between ions that are cytoplasmic and those that are mitochondrial.  The glass is half full!


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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


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=6×1030), and its high significance in the whole-genome study (P=4×109) 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.


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

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


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<5×108) with LDL-C reduction on rosuvastatin were identified at ABCG2LPA, 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=6.2×1020), 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=5.0×1041). 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.


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: 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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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


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


Circulation: Cardiovascular Genetics 2012; 5: 368-376

doi: 10.1161/ CIRCGENETICS.112.962746


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HOT TOPICS 2014: Heart – Medical 1
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Steven Nissen, MD – Cleveland Clinic
Clyde Yancy, MD – Northwestern University, Feinberg School of Medicine
Robert Califf, MD – Duke Medical Center
Elliott Antman, MD – BWH


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