Fall T, Xie W, Poon W, Yaghootkar H, Mägi R, GENESIS Consortium , Knowles JW, Lyssenko V, Weedon M, Frayling TM, Ingelsson E
Diabetes 64 (7) 2676-2684 [2015-07-00; online 2015-05-08]
The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C (β = -0.12, P = 0.03) and T2D and genetically determined lower LDL-C (β = -0.21, P = 5 × 10(-6)) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.