Human genetics suggests differing causal pathways from HMGCR inhibition to coronary artery disease and type 2 diabetes

BackgroundStatins lower low-density lipoprotein cholesterol (LDL-C) and reduce the risk of coronary artery disease (CAD). However, they also increase the risk of type 2 diabetes (T2D). MethodsWe consider genetic variants in the region of the HMGCR gene, which encodes the target of statins, and their associations with downstream consequences of statins. We use various statistical methods to identify causal pathways influencing CAD and T2D, and investigate whether these are the same or different for the two diseases. ResultsColocalization analyses indicated that LDL-C and body mass index (BMI) have distinct genetic predictors in this gene region, suggesting that they do not lie on the same causal pathway. Multivariable Mendelian randomization analyses restricted to variants in the HMGCR gene region revealed LDL-C and BMI as causal risk factors for CAD, and BMI as a causal risk factor for T2D, but not LDL-C. A Bayesian model averaging method prioritized BMI as the most likely causal risk factor for T2D, and LDL-C as the second most likely causal risk factor for CAD (behind ubiquinone). Colocalization analyses provided consistent evidence of LDL-C colocalizing with CAD, and BMI colocalizing with T2D; evidence was inconsistent for colocalization of LDL-C with T2D, and BMI with CAD. ConclusionsOur analyses suggest cardiovascular and metabolic consequences of statin usage are on different causal pathways, and hence could be influenced separately by targeted interventions. More broadly, our analysis workflow offers potential insights to identify pathway-specific causal risk factors that could provide possible repositioning or refinement opportunities for existing drug targets. Key messagesO_LIWe performed colocalization and cis-multivariable Mendelian randomization using genetic association data for variants in the HMGCR gene region to investigate causal pathways influencing coronary artery disease (CAD) and type 2 diabetes (T2D) C_LIO_LIOur analyses suggest that the impact of HMGCR inhibition on CAD risk is mediated by both low-density lipoprotein cholesterol (LDL-C) and body mass index (BMI), whereas for T2D, risk was mediated via BMI but not LDL-C. C_LIO_LIOur results suggest the possibility that targeted treatments could be developed to inhibit HMGCR in a more specific way that lowers CAD risk without increasing T2D risk. C_LI