Genome-wide association of lipid-lowering response to statins in combined study populations

Mathew J Barber, Lara M Mangravite, Craig L Hyde, Daniel I Chasman, Joshua D Smith, Catherine A McCarty, Xiaohui Li, Russell A Wilke, Mark J Rieder, Paul T Williams, Paul M Ridker, Aurobindo Chatterjee, Jerome I Rotter, Deborah A Nickerson, Matthew Stephens, Ronald M Krauss, Mathew J Barber, Lara M Mangravite, Craig L Hyde, Daniel I Chasman, Joshua D Smith, Catherine A McCarty, Xiaohui Li, Russell A Wilke, Mark J Rieder, Paul T Williams, Paul M Ridker, Aurobindo Chatterjee, Jerome I Rotter, Deborah A Nickerson, Matthew Stephens, Ronald M Krauss

Abstract

Background: Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs) contributing to this variation, we performed a combined analysis of genome-wide association (GWA) results from three trials of statin efficacy.

Methods and principal findings: Bayesian and standard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglyceride on a total of 3932 subjects using data from three studies: Cholesterol and Pharmacogenetics (40 mg/day simvastatin, 6 weeks), Pravastatin/Inflammation CRP Evaluation (40 mg/day pravastatin, 24 weeks), and Treating to New Targets (10 mg/day atorvastatin, 8 weeks). Genotype imputation was used to maximize genomic coverage and to combine information across studies. Phenotypes were normalized within each study to account for systematic differences among studies, and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies. Two SNP associations were assessed as having posterior probability greater than 50%, indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response. SNP rs8014194, located within the CLMN gene on chromosome 14, was strongly associated with statin-mediated change in total cholesterol with an 84% probability by Bayesian analysis, and a p-value exceeding conventional levels of genome-wide significance by frequentist analysis (P = 1.8 x 10(-8)). This SNP was less significantly associated with change in LDL-cholesterol (posterior probability = 0.16, P = 4.0 x 10(-6)). Bayesian analysis also assigned a 51% probability that rs4420638, located in APOC1 and near APOE, was associated with change in LDL-cholesterol.

Conclusions and significance: Using combined GWA analysis from three clinical trials involving nearly 4,000 individuals treated with simvastatin, pravastatin, or atorvastatin, we have identified SNPs that may be associated with variation in the magnitude of statin-mediated reduction in total and LDL-cholesterol, including one in the CLMN gene for which statistical evidence for association exceeds conventional levels of genome-wide significance.

Trial registration: PRINCE and TNT are not registered. CAP is registered at Clinicaltrials.gov NCT00451828.

Conflict of interest statement

Competing Interests: The Treating to New Targets Study (TNT) was funded by Pfizer. CH and AC are full time employees of Pfizer and were involved in analysis and interpretation of the data, as well as revisions to the manuscript. This relationship will not alter the author's ability to adhere to the PLoS data-sharing policy.

Figures

Figure 1. Posterior probability of association with…
Figure 1. Posterior probability of association with statin-mediated difference trait for total cholesterol at chromosome 14 region.
Gene structure indicated below graph. rs8014194, located in CLMN intron 1, was the most significantly associated variant.

References

    1. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama. 2001;285:2486–2497.
    1. Grundy SM. Approach to lipoprotein management in 2001 National Cholesterol Guidelines. Am J Cardiol. 2002;90:11i–21i.
    1. Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–239.
    1. Mangravite LM, Thorn CF, Krauss RM. Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J. 2006;6:360–374.
    1. Simon JA, Lin F, Hulley SB, Blanche PJ, Waters D, et al. Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. Am J Cardiol. 2006;97:843–850.
    1. Mangravite LM, Wilke RA, Zhang J, Krauss RM. Pharmacogenomics of statin response. Curr Opin Mol Ther. 2008;10:555–561.
    1. Krauss RM, Mangravite LM, Smith JD, Medina MW, Wang D, et al. Variation in the 3-hydroxyl-3-methylglutaryl-coenzyme A reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Circulation. 2008;117:1537–1544.
    1. Iakoubova OA, Sabatine MS, Rowland CM, Tong CH, Catanese JJ, et al. Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study. J Am Coll Cardiol. 2008;51:449–455.
    1. Kooner JS, Chambers JC, Aguilar-Salinas CA, Hinds DA, Hyde CL, et al. Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat Genet. 2008;40:149–151.
    1. Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt NP, et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med. 2008;358:1240–1249.
    1. Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2009;41:334–341.
    1. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41:56–65. Epub 2008 Dec 2007.
    1. Thompson JF, Hyde CL, Wood LS, Paciga SA, Hinds DA, et al. Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the Treating to New Targets (TNT) cohort. Circ Cardiovasc Genet. 2009;2:173–181.
    1. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40:955–962.
    1. Chasman DI, Pare G, Zee RYL, Parker AN, Cook NR, et al. Genetic loci associated with plasma concentration of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, and apolipoprotein B among 6382 white women in genome-wide analysis with replication. Circ Cardiovasc Genet. 2008;1:21–30.
    1. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008;40:161–169.
    1. Marchini J, Howie B, Myers S, McVean G, Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet. 2007;39:906–913.
    1. Servin B, Stephens M. Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet. 2007;3:e114.
    1. Guan Y, Stephens M. Practical issues in imputation-based association mapping. PLoS Genet. 2008;4:e1000279.
    1. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. Jama. 2001;286:64–70.
    1. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–1435.
    1. Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP, Jr, et al. Pharmacogenetic study of statin therapy and cholesterol reduction. Jama. 2004;291:2821–2827.
    1. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007;449:851–861.
    1. Stephens M, Balding DJ. Bayesian statistical methods for genetic association studies. Nature Reviews Genetics. 2009;10:681–690.
    1. Wakefield J. A Bayesian measure of the probability of false discovery in genetic epidemiology studies. Am J Hum Genet. 2007;81:208–227.
    1. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678.
    1. Reiner AP, Barber MJ, Guan Y, Ridker PM, Lange LA, et al. Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet. 2008;82:1193–1201.
    1. Pritchard JK, Rosenberg NA. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet. 1999;65:220–228.
    1. Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55:997–1004.
    1. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–909.
    1. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008;40:189–197.
    1. Clee SM, Zwinderman AH, Engert JC, Zwarts KY, Molhuizen HO, et al. Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease. Circulation. 2001;103:1198–1205.
    1. Goldberg IJ. Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis. J Lipid Res. 1996;37:693–707.
    1. Matzuk MM, Kumar TR, Bradley A. Different phenotypes for mice deficient in either activins or activin receptor type II. Nature. 1995;374:356–360.
    1. Yabe D, Brown MS, Goldstein JL. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci U S A. 2002;99:12753–12758.
    1. Cervino AC, Li G, Edwards S, Zhu J, Laurie C, et al. Integrating QTL and high-density SNP analyses in mice to identify Insig2 as a susceptibility gene for plasma cholesterol levels. Genomics. 2005;86:505–517.
    1. Ishisaki Z, Takaishi M, Furuta I, Huh N. Calmin, a protein with calponin homology and transmembrane domains expressed in maturing spermatogenic cells. Genomics. 2001;74:172–179.
    1. Hirosawa M, Nagase T, Ishikawa K, Kikuno R, Nomura N, et al. Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain. DNA Res. 1999;6:329–336.
    1. Wakefield J. Bayes factors for genome-wide association studies: comparison with P-values. Genet Epidemiol. 2009;33:79–86.
    1. Senn S. Statistical issues in drug development (statistics in practice: Wiley-Interscience. 2008:524 p.

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