The Asn9 variant of lipoprotein lipase is associated with the -93G promoter mutation and an increased risk of coronary artery disease

Jj, Kastelein; Be, Groenemeyer; Hallman, DM; Henderson, Howard; Pw, Reymer; Se, Gagné; Jansen, Hans; Jc, Seidell; Kromhout, Daan; Jukema, J. Wouter; Av, Bruschke; Boerwinkle, Eric; Hayden, Michael R.

doi:10.1034/j.1399-0004.1998.531530106.x

Cited by 44 publications

(38 citation statements)

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“…5 Finally, our findings are supported by a recent study of 762 Dutch men with coronary artery disease (37 double heterozygous carriers for the Ϫ93G/Asn9) and 296 controls (4 double heterozygous carriers), suggesting that double-heterozygous carrier status was associated with a nonsignificant elevation in plasma triglycerides, a decrease in HDL cholesterol, and an increased risk of coronary artery disease. 25 The increased OR for IHD and MI among double heterozygous carriers in the present study was statistically significant in men but not in women. Two explanations for this sex difference are possible.…”

Section: Discussionsupporting

confidence: 47%

Mutations in thelipoprotein lipaseGene Associated With Ischemic Heart Disease in Men

Wittrup

Tybjærg‐Hansen²,

Steffensen³

et al. 1999

ATVB

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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...

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Section: Discussionsupporting

confidence: 47%

Mutations in thelipoprotein lipaseGene Associated With Ischemic Heart Disease in Men

Wittrup

Tybjærg‐Hansen²,

Steffensen³

et al. 1999

ATVB

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“…17 DNA variants in the promoter of the LPL gene have been shown to be associated with changes in lipid metabolism leading to type 2 diabetes and its related traits. 12,18 Hence, this study was performed to evaluate the role of sequence variants in the promoter of LPL gene in relation to diabetes, obesity and related traits.…”

Section: Introductionmentioning

confidence: 99%

Association of lipoprotein lipase gene polymorphisms with obesity and type 2 diabetes in an Asian Indian population

et al. 2007

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Aims: Lipoprotein lipase (LPL), a pivotal enzyme in lipoprotein metabolism, catalyzes the hydrolysis of triglycerides of very lowdensity lipoproteins and chylomicrons. Assuming that the variants in the promoter of the LPL gene may be associated with changes in lipid metabolism leading to obesity and type 2 diabetes, we examined the role of promoter variants (-T93G and -G53C) in the LPL gene in an urban South Indian population. Methods: The study subjects (619 type 2 diabetic and 731 normal glucose-tolerant (NGT) subjects) were chosen from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The polymorphisms were genotyped using polymerase chain reaction-restriction-fragment length polymorphism (PCR-RFLP). Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies. Results: The two polymorphisms studied were not in LD. The -T93G was not associated with type 2 diabetes but was associated with obesity. 11.5% of the obese subjects (62/541) had the XG(TG þ GG) genotype compared with 6.4% of the nonobese subjects (52/809; P ¼ 0.001). The odds ratio for obesity for the XG genotype was 1.766 (95% CI: 1.19-2.63, P ¼ 0.005). Subjects with XG genotype also had higher body mass index and waist circumference compared with those with TT genotype. With respect to G53C, subjects with the XC(GC þ CC) genotype had 0.527 and 0.531 times lower risk for developing type 2 diabetes and obesity, respectively. Conclusions: Among Asian Indians, the -T93G SNP of the LPL gene is associated with obesity but not type 2 diabetes, whereas the -G53C SNP appears to be protective against both obesity and type 2 diabetes.

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“…Another meta-analysis, by Hokanson (34), determined the relative risk of CAD in combined Asp9Asn/ T-93G heterozygote carriers to be 2.0. In the Caucasian population, Asp9Asn is strongly linked to the promoter mutation T-93G, which also leads to decreased LPL activity (47,48). The effect of the mutation Asp9Asn on CAD without the additional promoter mutation has not been determined.…”

Section: Asp9asnmentioning

confidence: 99%

Lipoprotein lipase

Merkel

Eckel

Goldberg

2002

Journal of Lipid Research

464

113

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Lipoprotein lipase (LPL) regulates the plasma levels of triglyceride and HDL. Three aspects are reviewed. 1 ) Clinical implications of human LPL gene variations: common mutations and their effects on plasma lipids and coronary heart disease are discussed. 2 ) LPL actions in the nervous system, liver, and heart: the discussion focuses on LPL and tissue lipid uptake. 3 ) LPL gene regulation: the LPL promoter and its regulatory elements are described. -Merkel, M., R. H. Eckel, and I. J. Goldberg. Lipoprotein lipase: genetics, lipid uptake, and regulation.

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The Asn9 variant of lipoprotein lipase is associated with the -93G promoter mutation and an increased risk of coronary artery disease

Cited by 44 publications

References 0 publications

Mutations in thelipoprotein lipaseGene Associated With Ischemic Heart Disease in Men

Mutations in thelipoprotein lipaseGene Associated With Ischemic Heart Disease in Men

Association of lipoprotein lipase gene polymorphisms with obesity and type 2 diabetes in an Asian Indian population

Lipoprotein lipase

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