Mendelian randomization analysis supports the causal role of dysglycaemia and diabetes in the risk of coronary artery disease

Introduction Type 2 diabetes is a strong risk factor for coronary artery disease (CAD). However, the absence of a clear reduction in CAD by intensive glucose lowering in randomized controlled trials has fuelled uncertainty regarding the causal role of dysglycaemia and CAD. Objective To assess whether Mendelian randomization supports a causal role of dysglycaemia and diabetes for risk of CAD. Methods Effect size estimates of common genetic variants associated with fasting glucose (FG), glycated haemoglobin (HbA(1c)), and diabetes were obtained from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium and Diabetes Genetics Replication and Meta-Analysis consortia. The corresponding effect estimates of these single nucleotide polymorphisms (SNPs) on the risk of CAD were then evaluated in CARDIOGRAMplusC4D. Results SNPs associated with HbA(1c) and diabetes were associated with an increased risk of CAD. Using information from 59 genetic variants associated with diabetes, the causal effect of diabetes on the risk of CAD was estimated at an odds ratio (OR) of 1.63 (95% Confidence Interval (CI): 1.23-2.07; P = 0.002). On the other hand, nine genetic variants associated with HbA(1c) were associated with an OR of 1.53 per 1% HbA(1c) increase (95% CI: 1.14-2.05; P = 0.023) in the risk of CAD while this effect was non-significant among 30 genetic variants associated with FG per mmol/L (OR: 1.18, 95% CI: 0.97-1.42; P = 0.102). No significant differences were observed when categorizing genetic loci according to their effect on either beta-cell dysfunction or insulin resistance. Conclusions These Mendelian randomization analyses support a causal role for diabetes and its associated high glucose levels on CAD, and suggest that long-term glucose lowering may reduce CAD events.