Leveraging Human Genetics to Understand the Relation of LDL Cholesterol with Type 2 Diabetes.

Abstract

In a recent issue of the Journal of the American Medical Association , Lotta and colleagues used human genetic data to address the link of LDL cholesterol (LDL-C) 3 with type 2 diabetes (T2D) (1). They set out to investigate whether LDL-C–lowering alleles in or near genes encoding targets of 3 different lipid-lowering therapies (statins, PCSK9 inhibitors, and ezetimibe) were associated with risk of T2D. Human genetic studies have proven to be useful in predicting efficacy and adverse effects of perturbation of drug targets, such as cholesteryl ester transfer protein (CETP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitors. Previous studies have shown that LDL-C–lowering alleles in 3-hydroxy-3-methylglutaryl-CoA reductase ( HMGCR ), 4 the gene encoding the target of statins, are associated with lower risk of coronary heart disease (CHD), but also an increased risk of T2D. These observations are consistent with metaanalyses of randomized clinical trials of statins, which show that while statins decrease LDL-C concentrations and risk of cardiovascular events, they are also associated with a slightly increased risk of T2D. In contrast, individuals with familial hypercholesterolemia (FH) caused by mutations in low density lipoprotein receptor ( LDLR ) seem to be protected against T2D. Similarly, studies of variation in proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) have consistently predicted an effect of PCSK9 inhibitors on LDL-C–lowering and decreased risk of CHD, and a study published soon after the JAMA paper by Lotta et al. showed that PCSK9 variants associated with lower LDL-C also were associated with higher fasting glucose, body weight, and waist-to-hip ratio, and an increased risk of T2D (2). This observation contrasts to the initial (small) clinical trial data on PCSK9 inhibitors that have not shown significant effects on T2D risk. The observations of LDL-C–lowering alleles in both HMGCR and PCSK9 being associated with T2D risk is especially intriguing in the …