Published online before print February 12, 2009, doi: 10.1161/CIRCGENETICS.108.818062
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Original Articles |
Comprehensive Whole-Genome and Candidate Gene Analysis for Response to Statin Therapy in the Treating to New Targets (TNT) Cohort
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{at}amc.uva.nl or j.s.jansen@amc.uva.nl
Received September 9, 2008; accepted January 26, 2009.
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=6x10–30), and its high significance in the whole-genome study (P=4x10–9) 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.
Key Words: genetics • hypercholesterolemia • hydroxymethylglutaryl coenzyme A reductase inhibitors • myocardial infarction
CLINICAL PERSPECTIVE
The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.818062/DC1.
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