HDL Cholesterol and Risk of Type 2 Diabetes: A Mendelian Randomization Study

Abstract

Observationally, low levels of HDL cholesterol are consistently associated with increased risk of type 2 diabetes. Therefore, plasma HDL cholesterol increasing has been suggested as a novel therapeutic option to reduce the risk of type 2 diabetes. Whether levels of HDL cholesterol are causally associated with type 2 diabetes is unknown. In a prospective study of the general population (n = 47,627), we tested whether HDL cholesterol–related genetic variants were associated with low HDL cholesterol levels and, in turn, with an increased risk of type 2 diabetes. HDL cholesterol–decreasing gene scores and allele numbers associated with up to −13 and −20% reductions in HDL cholesterol levels. The corresponding theoretically predicted hazard ratios for type 2 diabetes were 1.44 (95% CI 1.38–1.52) and 1.77 (1.61–1.95), whereas the genetic estimates were nonsignificant. Genetic risk ratios for type 2 diabetes for a 0.2 mmol/L reduction in HDL cholesterol were 0.91 (0.75–1.09) and 0.93 (0.78–1.11) for HDL cholesterol–decreasing gene scores and allele numbers, respectively, compared with the corresponding observational hazard ratio of 1.37 (1.32–1.42). In conclusion, genetically reduced HDL cholesterol does not associate with increased risk of type 2 diabetes, suggesting that the corresponding observational association is due to confounding and/or reverse causation.