Genome-Wide Association of Lipid-Lowering Response to Statins in Combined Study Populations

Journal Article · 22 March 2010 · PLoS ONE

DOI: https://doi.org/10.1371/journal.pone.0009763 · OSTI ID:1627401

Barber, Mathew J. ^[1]; Mangravite, Lara M. ^[2]; Hyde, Craig L. ^[3]; Chasman, Daniel I. ^[4]; Smith, Joshua D. ^[5]; McCarty, Catherine A. ^[6]; Li, Xiaohui ^[7]; Wilke, Russell A. ^[8]; Rieder, Mark J. ^[4]; Williams, Paul T. ^[9]; Ridker, Paul M. ^[4]; Chatterjee, Aurobindo ^[3]; Rotter, Jerome I. ^[7]; Nickerson, Deborah A. ^[5]; Stephens, Matthew ^[10]; Krauss, Ronald M. ^[2]

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1. University of Chicago, IL (United States); DOE/OSTI
2. Children’s Hospital Oakland Research Institute, Oakland, CA (United States)
3. Pfizer Global Research and Development, Groton, CT (United States)
4. Harvard Medical School, Boston, MA (United States)
5. Washington University, St. Louis, MO (United States)
6. Marshfield Clinic Research Foundation, Marshfield, WI (United States)
7. Cedars-Sinai Medical Center, West Los Angeles, CA (United States)
8. Medical College of Wisconsin, Milwaukee, WI (United States)
9. Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
10. University of Chicago, IL (United States)

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. 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. 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.

• Research Organization: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
• Sponsoring Organization: Donald W. Reynolds Foundation; National Center for Research Resources (NCRR); National Institutes of Health (NIH); Pfizer; USDOE Office of Science (SC), Biological and Environmental Research (BER)
• Grant/Contract Number: AC02-05CH11231
• OSTI ID: 1627401
• Journal Information: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 3 Vol. 5; ISSN 1932-6203
• Publisher: Public Library of ScienceCopyright Statement
• Country of Publication: United States
• Language: English