Gene-statin interaction study identifies 9 loci that moderate statin effectiveness in blood lipids

Abstract Hyperlipidemia, and high low-density lipoprotein cholesterol (LDL-c) in particular, is a risk factor for atherosclerosis, myocardial infarction, and stroke. High LDL-c is primarily treated with HMG-CoA reductase inhibitors, commonly known as statins. If statins interfere with the genetic pathways that endogenously increase the risk for hyperlipidemia, gene-statin interactions may identify individuals that are more sensitive to these drugs. Accordingly, we performed genome-wide gene-statin interaction analyses for LDL-c and two related lipids: high-density lipoprotein cholesterol (HDL-c) and triglycerides (TG). Our results suggest statins selectively reduce LDL-c heritability. More specifically, we identified five genome-wide significant gene-statin interactions for LDL-c, two gene-interactions for HDL-c, and four gene-interactions for TG. Fifteen loci remained associated with LDL-c despite statin treatment, revealing treatment-resistant genotypes and suggesting additional genetic targets for drug development, enhancement, and repurposing. These results are an important step towards using targeted treatments for patients with hyperlipidemia.