Population pharmacogenetics of statin response. (360G-Wellcome-084726_Z_08_Z)

Recent advances in the understanding of human genome sequence variation, along with advances in genotyping technology and availability of large well- characterized clinical samples have transformed the study of the polygenic basis of common complex disease, with a growing list of robust and well validated novel disease loci being identified over the past year. We propose to extend this revolution to the area of pharmacogenetics and to define loci responsible for modulating inter-individual differences in response to the statin group of lipid lowering drugs. We plan to: (a) Perform whole genome association analysis in a large population of 4000 individuals with T2D who have been treated with statins. We will use sophisticated health informatics, only available in Tayside to define a longitudinal, repeated measures, cholesterol response to statin (b) Perform replication studies in-silico by data-sharing with clinical-trial based WGA studies (N>3000) to ensure robust identification of the principal response SNPs. (c) We will take the 150 variants with the most compelling association signals from this combined analysis through another round of replication involving another 2,000 Tayside- based samples. This design provides excellent power to detect a substantial fraction of common SNP-based variants with modest or large response effects with negligibly low false positive report probabilities; The applicants have a strong background in genetic epidemiology and have played a significant role in the replication of the T2D component of the WTCCC. This study is uniquely placed to deliver insights into the potential for personalized medicine, and to initiate the task of translating those findings into advances in clinical care.