Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The promoter sequence variant -480T in the hepatic lipase gene (LIPC) has been shown to be significantly associated with low post-heparin hepatic lipase activity. Some studies have also found that the -480T variant is associated with elevation in plasma HDL cholesterol. We tested for associations of LIPC -480T with plasma lipoprotein traits in samples taken from three distinct Canadian populations: 657 Alberta Hutterites, 328 Ontario Oji-Cree and 210 Keewatin Inuit. Plasma HL activity was not available for analyses. The LIPC -480T allele frequencies in these three groups, respectively, were 0.219, 0.527 and 0.383, and the prevalence of LIPC -480T/T homozygotes was, respectively, 0.042, 0.274 and 0.167. No significant association was found between LIPC -480T and plasma HDL cholesterol or apolipoprotein AI concentration, after adjusting for covariates including gender and body mass index. There was no consistent relationship between the population mean plasma HDL cholesterol concentration and the population LIPC -480T frequency. Our findings are consistent with the idea that the common promoter variation in LIPC, which has been reported to be associated with variation in post heparin HL activity and HDL triglyceride concentration, is not always associated with variation in plasma HDL cholesterol concentration, possibly due to yet unspecified environmental or genetic factors.
Atherosclerosis 1999 Sep
PMID:Absence of association between genetic variation in the LIPC gene promoter and plasma lipoproteins in three Canadian populations. 1048 98

The common -216G-->A and -480C-->T substitutions in the promoter region of the human hepatic lipase (LIPC) gene show high allelic association, and are correlated with decreased hepatic lipase activity and increased high-density lipoprotein cholesterol levels. To test the functionality of these substitutions, CAT-reporter assays were performed in HepG2 cells. LIPC (-650/+48) but not (-650/+61) promoter constructs showed transcriptional activity. LIPC (-650/+48) constructs with both -216A and -480T exhibited significantly lower promoter activity (-45%) than the wild-type form. Activities of -289/+48 constructs were not significantly affected by the -216G-->A substitution. The -480C/T site lies within a binding region for Upstream Stimulatory Factor (USF). Gel-shift assays showed that the binding affinity of USF protein for HL specific oligonucleotides was decreased four-fold by the -480C-->T substitution. However, promoter activity of the -650/+48 constructs was not significantly affected by the -480C-->T substitution alone. Co-transfection of HepG2 cells with USF(43) cDNA yielded a similar dose-dependent increase in activity of all -650/+48 constructs; the absolute difference in promoter activity increased but the relative difference between the variant promoter forms was maintained. Our studies demonstrate that the common LIPC promoter variation is functional, which explains the association of the -480T allele with a lower hepatic lipase activity in man.
Atherosclerosis 2001 Feb 15
PMID:Hepatic lipase promoter activity is reduced by the C-480T and G-216A substitutions present in the common LIPC gene variant, and is increased by Upstream Stimulatory Factor. 1125 63

Both hepatic lipase (HL) and apolipoprotein C-III (apoC-III) influence lipid metabolism. Common variation in promoters of both genes, LIPC -514C > T and APOC3 -482C > T, respectively, have been shown to affect plasma lipids and lipoproteins and glucose tolerance. We studied the interaction between both variants on parameters of glucose tolerance and lipid metabolism in 714 healthy young males participating in the second European Atherosclerosis Research Study (EARS-II). Approximately 18% of the subjects were carriers of at least one rare LIPC and APOC3 allele. These subjects exhibited, after fasting and oral fat loading, the highest values of triglyceride-rich lipoproteins, but there was no significant interactive effect on any lipid variable. However, interaction occurred on basal diastolic blood pressure (p =0.036) and, during oral glucose tolerance testing, on peak (p = 0.0065) and area under the curve for glucose (p =0.049), and insulin (p = 0.035). This resulted in the highest diastolic blood pressure and lowest glucose tolerance in carriers of at least one rare allele of both genes. Thus gene:gene interaction between LIPC and APOC3, even in these healthy young males, leads to changes in parameters that are typically characteristic of Syndrome-X.
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PMID:Interaction of the common apolipoprotein C-III (APOC3 -482C > T) and hepatic lipase (LIPC -514C > T) promoter variants affects glucose tolerance in young adults. European Atherosclerosis Research Study II (EARS-II). 1142 82

Genetic variation in the hepatic lipase (HL) gene (LIPC) promoter is an important determinant of HL activity in Caucasians. As HL activity is increased in patients with type 2 diabetes mellitus, we have investigated whether the -514 C-to-T polymorphism acted independently of type 2 diabetes to regulate HL activity. The frequency of this polymorphism and its effect on plasma HL activity and lipids were examined in 203 Chinese patients with type 2 diabetes and 205 controls. The frequency of the T allele was 0.343 and 0.376 in male and female diabetic patients, respectively, compared with 0.371 and 0.372 in male and female controls. The effect of LIPC genotype on HL activity was similar between men and women, and between diabetic patients and non-diabetic controls, with the lowest HL activity being found in those subjects with the TT genotype. On multivariate analysis, gender, LIPC genotype, the presence of type 2 diabetes and body mass index were independent predictors of HL activity, accounting for 22, 9, 5 and 3%, respectively, of the variance in HL activity (whole model adjusted R(2)=0.39, P<0.0001). The T allele was associated with higher high-density lipoprotein in the controls but not in the diabetic patients, and no associations were found between LIPC genotype and low-density lipoprotein subfractions in either groups. In conclusion, despite the higher frequency of the T allele in Chinese than in Caucasians, gender was the best predictor for HL activity, with LIPC gene polymorphism and type 2 diabetes making relatively smaller contributions to the variation in HL activity.
Atherosclerosis 2001 Jul
PMID:Effects of gender, hepatic lipase gene polymorphism and type 2 diabetes mellitus on hepatic lipase activity in Chinese. 1142 26

Trinidadians of South Asian origin have a high prevalence of cardiovascular disease and diabetes compared to Trinidadians of African origin. The degree to which these differences are related to genetic and/or environmental factors is unclear. To determine whether there might be a genetic basis for this difference in prevalence of deleterious phenotypes we examined allele frequencies for candidate genes in atherosclerosis and diabetes. We genotyped 81 consecutive neonates of African origin and 103 consecutive neonates of South Asian origin. We evaluated common polymorphisms in 11 candidate genes for atherosclerosis and diabetes. We found differences between the two subpopulations in the allele frequencies of several candidate genes, including APOE, LIPC, APOC3, PON1, PON2, and PPP1R3. However, the differences in the allele frequencies were not all consistent with the pattern of CHD expression between these two ethnic groups in adulthood. Thus, differences in genetic architecture alone may not explain the wide disparities in disease prevalence between these two subpopulations. It is very likely that environmental factors, or unmeasured genetic factors, influence the genetic susceptibility to disease in these subpopulations.
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PMID:Allele frequencies for candidate genes in atherosclerosis and diabetes among Trinidadian neonates. 1151 79

Some baboons accumulate appreciable amounts of large apoE-rich HDLs (HDL(1)) which are similar to those reported in humans with several different dyslipoproteinemias. We estimated HDL(1) cholesterol concentrations by gradient gel electrophoresis of serum samples obtained from 634 pedigreed baboons fed with three diets differing in levels of fat and cholesterol. The HDL(1) trait was highly heritable on each diet (0.390< or =h(2)< or =0.528). Segregation analyses yielded significant evidence that a single major gene plus polygenes affected HDL(1) on a high-fat low-cholesterol diet. The major gene explained approximately 56% of total trait variance and 90% of the additive genetic variance in HDL(1) levels in these baboons. Bivariate one-locus segregation analyses indicated that this major gene exerts significant pleiotropic effects on a number of traditional HDL traits on all three diets, including HDL size distributions, and concentrations of HDL-C, apoAI, and apoE. Linkage analyses showed that this major gene was not located in chromosomal regions that contain six candidate genes whose protein products are important to HDL metabolism (LCAT, CETP, APOA1, APOE, ABCA1, LIPC). Our results suggest this major gene in baboons plays a pivotal role in HDL metabolism, but is unlikely to code for any of the proteins previously implicated in studies of human HDL(1).
Atherosclerosis 2002 Aug
PMID:A major gene influences variation in large HDL particles and their response to diet in baboons. 1205 70

Insulin resistance is polygenic in origin, and can be observed at an early age. We have shown that variations in APOC3-482T>C and hepatic lipase (LIPC)-514C>T), individually (APOC3 alone) and interactively, modulate insulin and glucose levels after an OGTT in young healthy men participating in the European Atherosclerosis Research Study II (EARSII). Variation in the insulin gene (INS) variable number tandem repeat (VNTR) has been found to predispose to type 1 and type 2 diabetes. We have evaluated the HphI site 23 bp upstream of the INS gene (a surrogate marker for the VNTR) in EARSII (n=822), to determine if variation in INS contributes to insulin resistance. Carriers of the INS VNTR class III (HphI-) allele (frequency=0.29 (95%CI 0.27, 0.31)) had significantly higher 60-min insulin concentrations after the OGTT (P=0.014) and a marginally higher AUC insulin (P=0.07), compared to class I (HphI+) homozygotes. However, this effect on AUC insulin was modified by the level of physical activity, displaying significant gene:environment interaction (P=0.03). We tested for gene:gene interaction between the INS VNTR and both the LIPC-514C>T and APOC3-482T>C. While there was a significant interaction between INS VNTR and LIPC-514C>T on AUC glucose (P=0.013) and on AUC insulin (P=0.015), there was no interaction with APOC3-482T>C. Thus, despite a modest effect of the INS VNTR alone, the influence of this variant on insulin sensitivity was modified by gene:environment and gene:gene interactions, illustrating the biological complexity of insulin resistance.
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PMID:Interaction between insulin (VNTR) and hepatic lipase (LIPC-514C>T) variants on the response to an oral glucose tolerance test in the EARSII group of young healthy men. 1594 5

Cardiac rehabilitation programs (CR) are standard treatment for patients with coronary artery disease (CAD), yet a large variation in risk factor and lipoprotein changes exists. We investigated the role of three common genetic polymorphisms (CETP Taq1B, LIPC -514 and apo E) associated with alterations of lipoprotein metabolism, in patients before and after standardized CR. Three-hundred and seven patients were recruited for this study. DNA samples were collected and all three genotypes were determined for every patient. While the hepatic lipase LIPC promoter polymorphism and apo E genotype showed little or no correlation with response to CR, CETP Taq1B showed significant association with changes in plasma lipid and lipoproteins. The B1 homozygotes for CETP Taq1B genotype showed significant reduction in TC (-0.25+/-0.07, p < 0.01), LDL-C (-0.15+/-0.06, p < 0.050) and TG (-0.20+/-0.08, p < 0.05). B2 carriers showed no significant change in these parameters. HDL-C, exercise capacity and BMI improved independent of genotype. Individuals with the B1B1 genotype appear to respond well to CR, whereas B2 carriers exhibit marginal gains in lipoprotein risk factors. Although the B2 carriers had similar benefits in exercise capacity and weight reduction, long-term consequences of little or no change in lipoprotein risk factors require further investigation to establish appropriate management strategies.
Atherosclerosis 2005 Aug
PMID:Cholesterol ester transfer protein (CETP) Taq1B polymorphism influences the effect of a standardized cardiac rehabilitation program on lipid risk markers. 1603 91

Despite a higher prevalence of coronary heart disease risk factors, men of African origin have less coronary atherosclerosis, as measured by coronary calcification, than whites. In part, this is thought to be because of the less atherogenic lipoprotein profile observed in men of African origin, characterized by lower triglycerides and higher high-density lipoprotein (HDL) cholesterol. We hypothesized that the -514C>T polymorphism in the hepatic lipase gene (LIPC) plays a significant role in determining a less atherogenic lipoprotein profile observed in men of African origin. Previously conducted studies of the LIPC -514C>T polymorphism in African Americans may have been confounded by a higher level of European admixture; in addition, the results from these studies do not necessarily apply to other African populations because gene-environment interactions may differ. Thus, we compared nuclear magnetic resonance spectroscopy-measured lipoprotein subclass patterns and LIPC -514C>T genotypes in population-based samples of older white American (n = 532) and African American (n = 97) men from the Cardiovascular Health Study to those among older, less admixed, Afro-Caribbean men (n = 205) from the Tobago Health Study. Men of African origin had a more favorable lipoprotein profile than whites. In addition, levels of low-density lipoprotein cholesterol, total cholesterol, and triglyceride, and large and small very low-density lipoprotein, small low-density lipoprotein, as well as very low-density lipoprotein particle size, were remarkably lower in Afro-Caribbean men than in either African American or white men. The frequency of the LIPC -514T allele was much higher in Afro-Caribbeans (0.57) and in African Americans (0.49) than in whites (0.20). The -514T allele in both populations of African origin, but not in whites, was associated with elevated large HDL and greater HDL size. Our findings indicate that the higher frequency of the LIPC -514T allele found in men of African origin living in different environments significantly contributes to the more favorable distribution of HDL subclasses compared with whites.
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PMID:Lipoprotein subclass and particle size differences in Afro-Caribbeans, African Americans, and white Americans: associations with hepatic lipase gene variation. 1632 26

Dyslipidemia in the metabolic syndrome (MS) is considered to be one of the most important risk factors for atherosclerosis. It is characterized by hypertriglyceridemia, low concentration of plasma HDL-cholesterol, predominance of small dense LDL particles and an increased concentration of plasma apolipoprotein B (apoB). The pathogenesis of this type of dyslipidemia is partially explained, but its genetic background is still unknown. To evaluate the influence of cholesterol ester transfer protein (CETP) TaqIB polymorphism, lipoprotein lipase (LPL) PvuII and HindIII polymorphisms, hepatic lipase (LIPC) G-250A polymorphism and apolipoprotein C-III (APOC3) SstI gene polymorphism on lipid levels in dyslipidemia of the metabolic syndrome, 150 patients with dyslipidemia of metabolic syndrome were included. 96 % of patients had type 2 diabetes. The patients did not take any lipid lowering treatment. The exclusion criterion was the presence of any disease that could affect lipid levels, such as thyroid disorder, liver disease, proteinuria or renal failure. Gene polymorphisms were determined using the polymerase chain reaction and restriction fragment length polymorphisms. The genotype subgroups of patients divided according to examined polymorphisms did not differ in plasma lipid levels with the exception of apoB. The apoB level was significantly higher in patients with S1S1 genotype of APOC3 SstI polymorphism when compared with S1S2 group (1.10+/-0.26 vs. 0.98+/-0.21 g/l, p=0.02). Similarly, patients with H-H- genotype of LPL HindIII polymorphism had significantly higher mean apoB, compared with H+H- and H+H+ group (1.35+/-0.30 vs. 1.10+/-0.26 g/l, p=0.02). In the multiple stepwise linear regression analysis, apoB level seemed to be influenced by APOC3 SstI genotype, which explained 6 % of its variance. The present study has shown that the S1 allele of APOC3 SstI polymorphism and the H- allele of LPL HindIII polymorphism might have a small effect on apoB levels in the Central European Caucasian population with dyslipidemia of metabolic syndrome.
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PMID:Effect of gene polymorphisms on lipoprotein levels in patients with dyslipidemia of metabolic syndrome. 1634 38


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