Interactions between the -514C->T polymorphism of the hepatic lipase gene and lifestyle factors in relation to HDL concentrations among US diabetic men (original) (raw)
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Arteriosclerosis, Thrombosis, and Vascular Biology, 1999
Hepatic lipase is an important determinant of plasma HDL concentration and LDL subclass distribution and may therefore influence susceptibility to coronary artery disease (CAD). To assess the effect of genetic variation in hepatic lipase activity on CAD susceptibility, we determined the frequency of the Ϫ514T allele of hepatic lipase in white men with CAD and in controls who did not have CAD. In men with CAD, postheparin plasma hepatic lipase activity was 15% to 20% lower in heterozygotes and 30% lower in homozygotes for the Ϫ514T allele. Allele frequencies were similar in cases and controls, however, and were consistent with Hardy-Weinberg expectation in both groups. This finding was confirmed in a second group comprising cases with premature symptomatic CAD and controls who were free of disease. These data indicate that a primary decrease in hepatic lipase activity of as much as 30% does not influence susceptibility to CAD in white men. (Arterioscler Thromb Vasc Biol. 1999;19:1975-1978 Key Words: hepatic lipase Ⅲ risk factor Ⅲ HDL Ⅲ atherosclerosis Ⅲ polymorphism E pidemiological evidence suggests that high plasma con-
Journal of lipid research, 1999
Several studies have reported an inverse relationship between hepatic lipase activity and plasma high density lipoprotein (HDL) cholesterol concentrations. The purpose of the present study was to determine whether genetic and pharmacological variation in hepatic lipase activity alters the distribution of HDL subclasses. Two independent analytical methods (nuclear magnetic resonance and gradient gel electrophoresis) were used to compare HDL subclass distributions in 11 homozygotes for the -514C allele of hepatic lipase and in 6 homozygotes for the -514T allele. Mean hepatic lipase activity was 45 +/- 15 mmol. l(-1). hr(-1) in -514C homozygotes and 20 +/- 7 mmol. l(-1). hr(-1) in -514T homozygotes. Both analytical methods indicated that HDL(2b) was significantly higher and HDL(3a) was significantly lower in -514T homozygotes than in -514C homozygotes. No differences were noted in the other HDL fractions (HDL(2a), HDL(3b), and HDL(3c)). To determine the effects of increased hepatic lip...
Proceedings of The National Academy of Sciences, 1997
Genetic factors strongly inf luence interindividual variation in plasma high density lipoprotein cholesterol (HDL-C) levels, but the specific genetic polymorphisms that confer heritable variation in HDL-C levels have not been identified. In this study we examined the relationship between polymorphism in LIPC, the gene encoding hepatic lipase, and plasma HDL-C concentrations using a sequential approach comprising linkage analysis, DNA sequencing, and association studies. Linkage studies in 1465 American white subjects from 218 nuclear families indicated that allelic variation at, or closely linked to, the hepatic lipase gene accounts for a significant fraction (Ϸ25%) of the variation in plasma HDL-C concentrations. The hepatic lipase gene was then sequenced in selected individuals, and four novel polymorphisms were identified in the 5 f lanking region of the gene. These polymorphisms were in complete linkage disequilibrium and thus identified a single novel allele. Association studies indicated that heterozygosity for the rare allele was associated with modestly increased concentrations of plasma HDL-C (41 ؎ 11 vs. 37 ؎ 10 mg͞dl, P < 0.05) and apolipoprotein AI in men (131 ؎ 23 vs. 122 ؎ 21 mg͞dl, P < 0.05) but not in women. Homozygosity for the rare allele was associated with markedly higher plasma HDL-C (63 ؎ 3 mg͞dl) and apolipoprotein AI (153 ؎ 9 mg͞dl) concentrations in men. The results of the association study were replicated in a second, independently ascertained sample. Taken together, the results of the linkage and association studies provide strong evidence that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-C levels.
Hepatic lipase is involved in the metabolism of several lipoproteins and has a key role in reverse cholesterol transport. A common C-to-T substitution at position Ϫ514 of the hepatic lipase promoter has been associated with variations in plasma high density lipoprotein cholesterol (HDL-C) levels and hepatic lipase activity. The aim of the current study was to investigate the association of this polymorphism to lipoprotein levels in a population-based sample of 1314 male and 1353 female Framingham Offspring Study participants. In men and women, carriers of the Ϫ514T allele had higher HDL-C and apolipoprotein A-I (apoAI) concentrations compared with noncarriers. The higher HDL-C levels associated with the Ϫ514T allele was due to an increase in the HDL 2 -C subfraction, and this association was stronger in women compared with men (Pϭ0.0043 versus 0.0517). To gain further understanding about the metabolic basis of these effects, HDL and low density lipoprotein (LDL) subclass profiles were measured by using automated nuclear magnetic resonance spectroscopy and gradient gel electrophoresis, respectively. The association of the Ϫ514T allele with higher HDL-C levels seen in men and women was primarily due to significant increases in the large HDL subfractions (size range 8.8 to 13.0 nm). In contrast, there was no relationship between the hepatic lipase polymorphism at position Ϫ514 and the LDL particle size distribution after adjustment for familial relationships, age, body mass index, smoking, alcohol intake, use of -blockers, apoE genotype, and menopausal status and estrogen therapy in women. Moreover, multiple regression analyses suggested that the CϪ514T polymorphism contributed significantly to the variability of HDL particle size in men and women (PϽ0.04). Thus, our results show that the CϪ514T polymorphism in the hepatic lipase gene is associated with significant variations in the lipoprotein profile in men and women. (Arterioscler Thromb Vasc Biol. 2000;20:815-822.)
Advanced Biomedical Research, 2016
Background: Variations in the hepatic lipase (HL) gene are the potential candidate for coronary artery disease (CAD) especially in type 2 diabetes mellitus (T2DM) in diverse populations. We assessed the association of-514C/T and-250G/A polymorphisms in HL (LIPC) gene with CAD risk in Iranian population with type 2 diabetes. Materials and Methods: We evaluated 322 type 2 diabetic patients, 166 patients with normal angiograms as controls and 156 patients those identified with CAD undergoing their first coronary angiography as CAD cases. Genotyping of-514C/T and-250G/A polymorphisms in the promoter of the LIPC gene were studied by polymerase chain reaction (PCR)-restriction fragment length polymorphism technique. Results: Genotype distributions in CAD cases (73.7%, 20.5%, and 5.8% for −250G/A) and (62.2%, 32.7%, and 5.1% for-514C/T) were significantly different from those in controls (60.8%, 37.4%, and 1.8% for-250G/A) and (51.2%, 48.2%, and 0.6% for-514C/T). CAD cases had lower A-allele frequency than controls (0.131 vs. 0.196, P = 0.028). The odds ratio for the presence of-250 (GG + GA) genotype and A allele in CAD cases were 2.206 (95% confidence interval [CI] =1.33-3.65, P = 0.002) and 1.609 (95% CI = 1.051 −2.463, P = 0.029) respectively. Haplotype analysis demonstrated a significant association between especially LIPC double mutant (−250 A/-514 T) haplotype and presence of CAD. Conclusion: Our findings indicated that-250 G/A polymorphism rather than-514 C/T polymorphism of LIPC gene is more associated with the increased risk of CAD particularly in women with T2DM.
Journal of Lipid Research, 2004
Our goal was to further define the role of LPL gene polymorphisms in coronary heart disease (CHD) risk. We determined the frequencies of three LPL polymorphisms (D9N, N291S, and S447X) in 899 men from the Veterans Affairs HDL Intervention Trial (VA-HIT), a study that examined the potential benefits of increasing HDL with gemfibrozil in men with established CHD and low high density lipoprotein cholesterol (HDL-C; р 40 mg/dl), and compared them with those of men without CHD from the Framingham Offspring Study (FOS). In VA-HIT, genotype frequencies for LPL D9N, N291S, and S447X were 5.3, 4.5, and 13.0%, respectively. These values differed from those for men in FOS having an HDL-C of Ͼ 40, who had corresponding values of 3.2% ( P ؍ 0.06), 1.5% ( P Ͻ 0.01), and 18.2% ( P Ͻ 0.01). On gemfibrozil, carriers of the LPL N9 allele in VA-HIT had lower levels of large LDL ( ؊ 32%; P Ͻ 0.01) but higher levels of small, dense LDL ( ؉ 59%; P Ͻ 0.003) than did noncarriers. Consequently, mean LDL particle diameter was smaller in LPL N9 carriers than in noncarriers (20.14 ؎ 0.87 vs. 20.63 ؎ 0.80 nm; P Ͻ 0.003). In men with low HDL-C and CHD: 1 ) the LPL N9 and S291 alleles are more frequent than in CHD-free men with normal HDL-C, whereas the X447 allele is less frequent, and 2 ) the LPL N9 allele is associated with the LDL subclass response to gemfibrozil. -Brousseau, M
Nutrition, Metabolism and Cardiovascular Diseases, 2008
Background and aims: Hepatic lipase (HL) catalyzes the hydrolysis of triglycerides and phospholipids from lipoproteins, and promotes the hepatic uptake of lipoproteins. A common G-250A polymorphism in the promoter of the hepatic lipase gene (LIPC) has been described. The aim was to study the effects of the G-250A polymorphism on HL activity, serum lipid profile and insulin sensitivity. Methods and results: Altogether 151 healthy subjects (age 49 AE 8 years, BMI 26.5 AE 3.0 kg/m 2) were randomly assigned for 3 months to an isoenergetic diet containing either a high proportion of saturated fatty acids (SFA diet) or monounsaturated
The American journal of clinical nutrition, 2005
Gene-nutrient interactions affecting hepatic lipase (HL) activity may contribute to the interindividual variability of the cardiovascular disease risk associated with dietary fat intake. We determined the associations of dietary fat intake with postheparin HL activity and the possible modifying effect of the HL -480C-->T polymorphism on these associations. Subjects were recruited from participants in the 2000-2001 follow-up examination of the Hoorn Study. HL activity was determined in postheparin plasma in a sample of 211 men and 218 women aged 60-87 y. Information about dietary intake of the participants was obtained with a validated food-frequency questionnaire. Linear regression was performed, adjusted for age. Total dietary fat was positively associated with HL activity (standardized beta: 0.11; 95% CI: 0.02, 0.21), and this association was also seen for saturated fat (0.10; 0.01, 0.20) and monounsaturated fatty acid (0.10; 0.01, 0.19). We observed a significant interaction o...
The Journal of Clinical Endocrinology & Metabolism, 2009
Context: Hepatic lipase influences metabolism of high-density lipoprotein (HDL), a risk factor for ischemic cardiovascular disease (ICD: ischemic heart disease and ischemic cerebrovascular disease).Objective: We tested the hypothesis that genetic variation in the hepatic lipase genetic variants V73M, N193S, S267F, L334F, T383M, and −480c>t influence levels of lipids, lipoproteins, and apolipoproteins and risk of ICD.Design: For the cross-sectional study, we genotyped 9003 individuals from the Copenhagen City Heart Study; hereof were 8971 individuals included in the prospective study, 1747 of whom had incident ICD during 28 yr of follow-up. For the case-control studies, 2110 ischemic heart disease patients vs. 4899 controls and 769 ischemic cerebrovascular disease patients vs. 2836 controls, respectively, were genotyped. Follow-up was 100% complete.Results: HDL cholesterol was higher by 0.21 mmol/liter in S267F heterozygotes, by 0.06 mmol/liter in −480c>t heterozygotes, and by ...