Gene-drug interactions identify genomic loci that enhance statin effectiveness in lowering LDL cholesterol.

Abstract

Hyperlipidemia, and high low-density lipoprotein cholesterol (LDL-c) in particular, is a risk factor for cardiovascular disease, including atherosclerosis, myocardial infarction, and stroke. Nearly 200 million people worldwide take HMG-CoA reductase inhibitors, commonly known as statins, to lower their LDL-c. If statins interfere with the genetic pathways that endogenously increase the risk for hyperlipidemia, gene-statin interactions may identify genomic variants, and thereby individuals with those genotypes, that are particularly sensitive to these medications. We performed a series of genome-wide gene-statin interaction analyses in the UK Biobank for LDL-c and two related lipids: high-density lipoprotein cholesterol (HDL-c) and triglycerides (TG). We identified five genome-wide significant gene-statin interactions for LDL-c, two interactions for HDL-c, and four interactions for TG. Importantly, only the SNP-based heritability of LDL-c was reduced by statin use. Using data from All of Us, we replicated all five significant gene-statin interaction loci for LDL-c in the European-like ancestry sample, two loci in the Americas-like ancestry sample, and one locus in the African-like ancestry sample. We also identified fifteen loci that remained associated with LDL-c despite statin treatment, highlighting potential additional genetic targets for drug development, enhancement, and repurposing. These loci include gene-targets for the recently developed hyperlipidemia drug class (PCSK9 inhibitors) validating our approach to finding new treatments. These results are an important step towards personalized medicine for patients with hyperlipidemia. Author SummaryHigh cholesterol raises the risk of heart attacks and strokes and nearly 200 million people worldwide take statins to lower it. While statins work for nearly everyone, they work better for some people than others. We examined how genetic differences enhance the effectiveness of statin medication as a step toward enhancing personalized medicine for those with high cholesterol. By analyzing genetic and health data from about 390,000 people, we found that statins primarily disrupt the link between genes and LDL or "bad" cholesterol levels. Across the genome, statins reduce the impact of genes on LDL-c levels, but not other blood lipids like HDL-c or triglycerides. For LDL-c specifically, we found five regions where genetic differences increase the effectiveness of statins. People with the protective genetic variants are expected to see greater cholesterol reduction with statin use. We confirmed four of the five findings in European-like ancestry samples, with partial replication in Americas-like and African-like ancestry samples (two variants and one variant, respectively). We also found 15 genomic regions where cholesterol stays high despite statin treatment. These genomic regions could be targets for new or enhanced cholesterol medications. In fact, a newer drug class targets one of these regions supporting our approach to finding new treatments.