Variants of ADAMTS1 modify the effectiveness of statins in reducing the risk of myocardial infarction

Objective To investigate the influence of tagging single-nucleotide polymorphisms (SNPs) within candidate genes involved in the putative anti-inflammatory effects of statins on the effectiveness of statins in reducing the risk of myocardial infarction (MI). Methods We conducted a case-control study in a population-based registry of pharmacy records linked to hospital discharge records (PHARMO). Cases and controls were selected from within a hypercholesterolemic cohort. Cases were hospitalized for MI, whereas controls were not. Logistic regression analysis was used to investigate pharmacogenetic interactions. Results The study population comprised 668 cases and 1217 controls. We genotyped 84 SNPs in 24 genes. The effectiveness of statins was found to be modified by seven SNPs in three genes. Five out of six SNPs that were selected in the A disintegrin and metallopeptidase with thrombospondin motif type I (ADAMTS1) gene were associated with a modified response to statins, three of which were in strong linkage disequilibrium. The strongest interaction was found for ADAMTS1 rs402007. Homozygous carriers of the variant allele had the most benefit from statins [adjusted odds ratio (OR): 0.10, 95% confidence interval (CI): 0.03-0.35], compared with heterozygous (OR: 0.43, 95% CI: 0.24-0.51) and homozygous wildtype carriers (OR: 0.49, 95% CI: 0.32-0.57). Conclusion Consistent with earlier findings, polymorphisms within the ADAMTS1 gene influenced the effectiveness of statins in reducing the risk of MI. Other pharmacogenetic interactions with SNPs in the TNFRSF1A and ITGB2 genes were established and the confirmation will be pursued in future studies. Pharmacogenetics and Genomics 20:766-774 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.