Comprehensive Whole Genome and Candidate Gene Analysis for Response to Statin Therapy in TNT Cohort

Background —Statins are effective at lowering LDL-C and reducing risk of cardiovascular disease, but variability in response is not well understood. To address this, 5745 individuals from the 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 —291,988 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 LDL-C, HDL-C, 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 LDL-C response followed by one 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 LDL-C 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.