Abstract 12582: Genetically Reduced High-Density Lipoprotein Cholesterol and Risk of Type 2 Diabetes: A Mendelian Randomization Study
Introduction: Epidemiologically low levels of high-density lipoprotein (HDL) cholesterol consistently associate with increased risk of type 2 diabetes. The causal nature of this association is unclear.
Hypothesis: Using Mendelian randomization, we tested whether low levels of HDL cholesterol causally influence type 2 diabetes.
Methods: In a prospective study of 47,627 individuals from the general population, we tested whether low HDL cholesterol predicted risk of type 2 diabetes. Using a combined genotype score or allele numbers of five HDL genes, we tested whether genetic variants associated with low HDL cholesterol levels also associated with an increased risk of type 2 diabetes.
Results: Risk of type 2 diabetes increased with decreasing levels of HDL cholesterol (P for trend=3x10-58). HDL cholesterol decreasing gene scores and allele numbers associated with up to -13% and -20% decreases in HDL cholesterol levels. The corresponding theoretically predicted hazard ratios (HRs) for type 2 diabetes were 1.44 (1.38-1.52) and 1.77 (1.61-1.95), while the genetic estimates were non-significant (P for trend: 0.41 and 0.55). Genetic risk ratios for a 50% reduction in HDL cholesterol were 0.66 (0.33-1.33) and 0.74 (0.37-1.47) for HDL cholesterol decreasing gene scores and allele numbers, respectively, compared to the corresponding observational HR=3.81 (3.30-4.39) (P for comparison: 2x10-6 and 6x10-6, respectively).
Conclusions: Genetically reduced HDL cholesterol does not associate with an increased risk of type 2 diabetes, suggesting that the level of HDL cholesterol is not a causal risk factor for type 2 diabetes.
Author Disclosures: C.L. Haase: None. A. Tybjaerg-Hansen: None. B.G. Nordestgaard: None. R. Frikke-Schmidt: None.
- © 2014 by American Heart Association, Inc.