Pleiotropic Effects of Lipid Genes on Plasma Glucose, HbA1c, and HOMA-IR Levels

Dyslipidemia is strongly associated with raised plasma glucose levels and insulin resistance (IR), and genome-wide association studies have identified 95 loci that explain a substantial proportion of the variance in blood lipids. However, the loci's effects on glucose-related traits are largely unknown. We have studied these lipid loci and tested their association collectively and individually with fasting plasma glucose (FPG), glycated hemoglobin (HbA(1c)), and IR in two independent cohorts: 10,995 subjects from LifeLines Cohort Study and 2,438 subjects from Prevention of Renal and Vascular Endstage Disease (PREVEND) study. In contrast to the positive relationship between dyslipidemia and glucose traits, the genetic predisposition to dyslipidemia showed a pleiotropic lowering effect on glucose traits. Specifically, the genetic risk score related to higher triglyceride level was correlated with lower levels of FPG (P = 9.6 x 10(-10) and P = 0.03 in LifeLines and PREVEND, respectively), HbA(1c) (P = 4.2 x 10(-7) in LifeLines), and HOMA of estimated IR (P = 6.2 x 10(-4) in PREVEND), after adjusting for blood lipid levels. At the single nucleotide polymorphism level, 15 lipid loci showed a pleiotropic association with glucose traits (P < 0.01), of which eight (CETP, MLXIPL, PLTP, GCKR, APOB, APOE-C1-C2, CYP7A1, and TIMD4) had opposite allelic directions of effect on dyslipidemia and glucose levels. Our findings suggest a complex genetic regulation and metabolic interplay between lipids and glucose.