A Common Mutation in the Lipoprotein Lipase Gene Promoter, −93T/G, Is Associated With Lower Plasma Triglyceride Levels and Increased Promoter Activity In Vitro

Hall, Stephen; Chu, Grace; Miller, George; Cruickshank, Kennedy; Cooper, J.; Humphries, Steve E.; Talmud, Philippa J.

doi:10.1161/01.atv.17.10.1969

Cited by 44 publications

(73 citation statements)

References 28 publications

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“…In both cell types, the mutant G allele was associated with a modest 20% lower transcription activity than the wild type T allele. This modest effect (20% difference in promoter activity) is predicted from a common variant and is similar to the effect size of 18-24% difference in promote activity reported earlier for a common LPL promoter variant (−93 T/G) [28]. These data strongly suggest that human LPL promoter controls LPL expression in conjunction with regulatory elements present in intron 8 and confirm the original observation made by Enerbäck et al [25].…”

Section: Discussionsupporting

confidence: 89%

Functional significance of lipoprotein lipase HindIII polymorphism associated with the risk of coronary artery disease

et al. 2008

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Lipoprotein Lipase (LPL) plays a pivotal role in lipid metabolism by hydrolyzing triglyceride (TG) rich lipoprotein particles. Abnormalities in normal LPL function are associated with the risk of coronary artery disease (CAD). A number of genetic variants have been identified in the LPL gene that affects different functions of the LPL protein. A common HindIII polymorphism in intron 8 (T/ G) of the LPL gene has been found to be associated with altered plasma TG and HDL-cholesterol, and CAD risk in several studies, but its functional significance is unknown. It has been shown that certain intronic sequence contain regulatory elements that are important for transcription and translational regulation of a gene. In this study we tested the hypothesis that this polymorphism affects the binding site of a transcription factor that regulates the transcription of LPL gene. Electrophoretic mobility shift assays revealed that the HindIII site binds to a transcription factor and that the mutant allele has lower binding affinity than the wild type allele. Transcription assays containing the entire intron 8 sequence along with full-length human LPL promoter were carried out in COS-1 and human vascular smooth muscle cells. The mutant allele was associated with significantly decreased luciferase expression level compared to the wild type allele in both the muscle (3.394 ± 0.022 vs. 4.184 ± 0.028; P=4.7 × 10 −6 ) and COS-1 (11.603 ± 0.409 vs. 14.373 ± 1.096; P<0.0001) cells. In conclusion, this study demonstrates for the first time that the polymorphic HindIII site in the LPL gene is functional because it affects the binding of a transcription factor and it also has an impact on LPL expression.

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Section: Discussionsupporting

confidence: 89%

Functional significance of lipoprotein lipase HindIII polymorphism associated with the risk of coronary artery disease

et al. 2008

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“…24 Using a human adrenal cell line, NCIH295, which has been shown to secrete LPL, 25 a similar (18%) increase in luciferase activity was seen with the G allele. 24 Although this variant was not associated with altered lipid profile in this study population, the association of this promoter variant with different measures LPL gene variants, obesity and type 2 diabetes in Asian Indians V Radha et al of obesity suggests it could be an important contributor to obesity and type 2 diabetes in this ethnic group. The À53 G-C promoter polymorphism of the LPL gene was found to be a rare variant in Dutch, Black and Chinese populations.…”

Section: Discussionmentioning

confidence: 88%

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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“…8,28 -35 In favor of the Asp9Asn substitution is the change in charge of LPL induced by the substitution of aspartate with asparagine: located in the N-terminal end of LPL, this amino acid substitution may influence catalytic activity. 3 Furthermore, in contrast to whites, single heterozygotes for the T(Ϫ93)3 G mutation were found in 50% to 60% of 161 black South Africans 34 and of 81 AfroCaribbeans, 35 and in these populations the Ϫ93G allele was found to be associated with lower plasma triglyceride levels compared with carriers of the Ϫ93T allele; this suggests that the Asp9Asn substitution may be the determining factor for the elevation of plasma triglycerides in whites.…”

Section: Discussionmentioning

confidence: 99%

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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A Common Mutation in the Lipoprotein Lipase Gene Promoter, −93T/G, Is Associated With Lower Plasma Triglyceride Levels and Increased Promoter Activity In Vitro

Cited by 44 publications

References 28 publications

Functional significance of lipoprotein lipase HindIII polymorphism associated with the risk of coronary artery disease

Functional significance of lipoprotein lipase HindIII polymorphism associated with the risk of coronary artery disease

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

Mutations in thelipoprotein lipaseGene Associated With Ischemic Heart Disease in Men

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