Abstract and Introduction
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.
Low levels of HDL cholesterol are consistently associated with increased risk of type 2 diabetes in epidemiological studies.[1,2] Therefore plasma HDL cholesterol increasing has been suggested as a novel therapeutic option to reduce risk of type 2 diabetes.[3–5] Low levels of HDL cholesterol and high levels of triglycerides are part of the diabetic dyslipidemia,[6–8] and high levels of triglycerides have recently been shown to be a marker of type 2 diabetes rather than playing a causal role. Whether low levels of HDL cholesterol causally influence the risk of type 2 diabetes remains to be determined.
Experimental evidence suggests that levels of HDL cholesterol may contribute to the pathophysiology of type 2 diabetes through direct effects on plasma glucose levels. Indeed, HDL cholesterol stimulates pancreatic β-cell insulin secretion and modulates glucose uptake in skeletal muscle in different experimental and human settings.[10–13] However, genetic data from humans and mice relating genes influencing HDL cholesterol levels with glycemic control and risk of type 2 diabetes are conflicting.[11,12,14–17] Furthermore, genome-wide association studies have not identified associations between such HDL cholesterol–related genes and risk of type 2 diabetes.[18,19]
Despite consistent observational evidence to support an association between low HDL cholesterol and type 2 diabetes, such data cannot overcome the problems of confounding and reverse causation, and therefore do not have the ability to establish causality. One useful method to help untangle causality is Mendelian randomization, where HDL cholesterol–related genetic variants are used as unconfounded proxies for lifelong low HDL cholesterol levels to test a potential causal association with type 2 diabetes risk.
We tested the following hypotheses in 47,627 individuals from the general population: 1) low HDL cholesterol levels are associated with the increased risk of type 2 diabetes in epidemiological studies; 2) HDL cholesterol–related genetic variants affect the levels of HDL cholesterol; 3) HDL cholesterol–related genetic variants, causing lifelong low levels of HDL cholesterol, were associated with the risk of type 2 diabetes to the extent predicted by the observational data; and 4) HDL cholesterol levels are causally associated with the risk of type 2 diabetes.
Diabetes. 2015;64(9):3328-3333. © 2015 American Diabetes Association, Inc.