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 1.4...