G-250A substitution in promoter of hepatic lipase gene is associated with dyslipidemia and insulin resistance in healthy control subjects and in members of families with familial combined hyperlipidemia

Low activity of hepatic lipase (HL) has been associated with high levels of triglycerides and high density lipoproteins, but the association of the HL promoter variants with insulin sensitivity has not been investigated. Ther efore, in this study, the relationship of the G-250A promoter variant of th e HL gene to the rates of insulin-stimulated glucose uptake measured by the hyperinsulinemic euglycemic clamp was investigated in 110 control subjects (82 men and 28 women, aged 50.7 +/- 7.6 [mean +/- SD] years, body mass ind ex 26.1 +/- 3.6 kg/m(2)) and in 105 first-degree relatives (65 men and 30 w omen, aged 37.8 +/- 16.0 years, body mass index 26.9 +/- 5.3 kg/m(2)) of 34 families with familial combined hyperlipidemia (FCHL). The A-250 allele of the HL promoter was associated with low rates of insulin-stimulated whole- body nonoxidative glucose disposal in control subjects (41.1 +/- 12.7 mu mo l(.)kg(-1.)min(-1) in subjects with the G-250G genotype. 36.9 +/- 13.1 mu m ol(.)kg(-1.)min(-1) in subjects with the G-250A genotype, and 29.9 +/- 13.5 mu mol(.)kg(-1.)min(-1) in subjects with the A-250A genotype; P = 0.012 ad justed for age and sex) and with low rates of insulin-stimulated whole-body glucose oxidation in FCHL family members (16.7 +/- 4.2 versus 15.0 +/- 3.4 versus 14.1 +/- 4.4 mu mol(.)kg(-1.)min(-1), P = 0.034), In addition, the A-250 allele was associated with high levels of fasting insulin (P = 0.047) , very low density lipoprotein cholesterol (P = 0.007), and total (P = 0.00 9) and very low density lipoprotein (P = 0.005) triglycerides in control su bjects and with high levels of low density lipoprotein triglycerides (P = 0 .001) in FCHL family members (n = 340). We conclude that the G-250A promote r variant of the HL gene is associated with dyslipidemia and insulin resist ance. Mechanisms via which this polymorphism could affect insulin sensitivi ty remain to be elucidated.