Mutations in thelipoprotein lipaseGene Associated With Ischemic Heart Disease in Men

Abstract

Abstract-The aim of this study was to test the hypothesis that the Asp9Asn substitution and the T(Ϫ93)3 G mutation in the promoter of the lipoprotein lipase gene affect plasma lipid levels and thereby the risk of ischemic heart disease (IHD). We genotyped 9033 men and women from a general population sample and 940 patients with IHD. The frequency of both the G allele and the Asn9 allele in the general population sample was Ϸ0.015 for both men and women. These 2 mutations appeared together in 95% of carriers. The average triglyceride-raising effect associated with double heterozygosity for the T(Ϫ93)3 G mutation and the Asp9Asn substitution was 0.28 mmol/L (Pϭ0.004) and 0.16 mmol/L (Pϭ0.10) in men and women, respectively. On logistic regression analysis allowing for age, the risk of IHD for double heterozygous men and women was increased 90% (95% confidence interval [CI], 20% to 200%) and 30% (95% CI, Ϫ40% to 170%), respectively, compared with noncarriers. When, in addition, other conventional cardiovascular risk factors were allowed for, the risk of IHD for double heterozygous men and women was increased 70% (95% CI, 0% to 190%) and 20% (95% CI, Ϫ50% to 180%), respectively. Of the overall risk of IHD in men in the general population, the fraction attributable to double heterozygosity was 3%, similar to the 5% attributable to diabetes mellitus. These results demonstrate that the Asp9Asn substitution is in linkage disequilibrium with the T(Ϫ93)3 G mutation and that the double-heterozygous carrier status is associated with elevated plasma triglycerides and an increased risk of IHD in men. Key Words: atherosclerosis Ⅲ coronary disease Ⅲ genes Ⅲ enzymes Ⅲ lipids L ipoprotein lipase (LPL) hydrolyzes triglycerides contained in the core of both chylomicrons and VLDLs, thus causing these particles to be transformed into chylomicron remnants and IDLs/LDLs, respectively; excess surface molecules are transferred to the HDL fraction. 1,2 More than 60 different rare, structural mutations in the lipoprotein lipase gene have been described in either the homozygote or compound heterozygote form in patients with severe hypertriglyceridemia and reduced HDL levels. 1,3 As a result of such mutations, the enzyme is either not produced or becomes catalytically ineffective. In a previous study including 10 207 individuals, we demonstrated that 1 of these rare mutations, causing the Gly188Glu substitution, in the heterozygous state is associated with increased plasma triglyceride levels, reduced HDL cholesterol levels, and a 5-fold increase in risk of ischemic heart disease (IHD). 4 In another recent study of the same individuals, we observed that the more common Asn291Ser substitution in LPL in the heterozygous state was associated with an increase in plasma triglycerides mainly in women, a decrease in plasma HDL cholesterol in both sexes, and a 2-fold increase in risk of IHD in women. 5 A different class of genetic variation is represented by regulatory mutations. 6 Such mutations may either increase or reduce the level of mRNA gene t...

Quantitative Trait Loci Near the Insulin-Degrading Enzyme (IDE) Gene Contribute to Variation in Plasma Insulin Levels

“…Second, both of these studies suggest effects either exclusively or predominantly in male subjects. Numerous studies have detected genetic effects exclusively in men (20,21), and sex specificity may be a major confounding factor in genetic analyses (22). Third, the marker that was in strongest association with quantitative traits related to Alzheimer's disease in our recent study (13) was rs2251101 (from among 26 markers).…”

Lipoprotein lipase

“…Of mutations reducing LPL activity, Asn291Ser is the most common; the Caucasian population has 2-5% heterozygote carriers (20). Less common mutations are Asp9Asn (1.5%) (21) and Gly188Glu (0.06%) (22). The French Canadian population has an especially high rate of LPL mutation carriers, up to 17% (Pro207Leu, Gly188Glu, and Asp250Asn) (23).…”

“…However, a hyperchylomicronemic patient who was heterozygous for Tyr262His and Asp9Asn has been reported (43). Asp9Asn has been linked frequently to hypertriglyceridemia, low HDL, small dense LDL, FCHL and increased risk of CAD, especially if combined with other risk factors (21,(44)(45)(46). According to a meta-analysis by Wittrup, Tybjaerg-Hansen, and Nordestgaard (33), Asp9Asn leads to a 20% increase in TGs, 0.8 mmol/l (3.2 mg/dl) decrease in HDL, and 1.4-fold increased risk of ischemic heart disease, borderline significant.…”

The Proline 12 Alanine Substitution in the Peroxisome Proliferator–Activated Receptor-γ2 Gene Is Associated With Lower Lipoprotein Lipase Activity in Vivo

“…Lower plasma LPL activity as well as mutations and polymorphisms in the LPL gene have been suggested to be proatherogenic (14)(15)(16) and associated with endothelial dysfunction (17). LPL activity in postheparin plasma is difficult to measure and appears to be an insensitive measure of CAD risk (18).…”