G-250A Substitution in Promoter of Hepatic Lipase Gene Is Associated With Dyslipidemia and Insulin Resistance in Healthy Control Subjects and in Members of Families With Familial Combined Hyperlipidemia

Pihlajamäki, Jussi; Karjalainen, Leena; Karhapää, Pauli; Vauhkonen, Ilkka; Taskinen, Marja‐Riitta; Deeb, Samir S.; Laakso, Markku

doi:10.1161/01.atv.20.7.1789

Cited by 65 publications

(45 citation statements)

References 64 publications

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“…The occurrence of NAFLD may also be influenced by lipoprotein lipase (LPL) activity, related inter alia to its genetic polymorphism. Several described LPL gene polymorphisms are associated with a higher incidence of insulin resistance and cardiovascular risk factors, but others could exert protective effects [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Niealkoholowe stłuszczenie wątroby u kobiet z zespołem wielotorbielowatych jajników — aspekty kliniczne i metaboliczne oraz polimorfizm genu lipazy lipoproteinowej

Bohdanowicz-Pawlak

Lenarcik-Kabza

Brona

et al. 2015

Endokrynologia Polska

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Introduction:The aim was to assess associations among PCOS and NAFLD, the lipoprotein lipase polymorphism gene, and metabolic disorders in PCOS. Material and methods:In 184 women with PCOS and 125 healthy, premenopausal volunteers, sex steroids, lipids, glucose, insulin, aminotransferases, free androgen index (FAI), HOMA-IR and E2/T were calculated. Hepatic steatosis was determined by ultrasound. Whole genomic DNA was isolated from blood leucocytes. Lipoprotein lipase polymorphisms rs268 and rs328 were analysed by polymerase chain reaction (PCR) and minisequencing. Results: 57.6% of PCOS women had NAFLD, while women without PCOS had NAFLD in 49.6%. PCOS-NAFLD women had higher BMI, WHR and waist circumference compared to women with PCOS without NAFLD and women without PCOS. PCOS-NAFLD women had lower SHBG, E2/T ratio, and higher FAI compared to other groups. ALT levels were higher in PCOS women with NAFLD compared to other groups. PCOS women with and without NAFLD had higher fasting glucose and insulin and HOMA compared to women without PCOS. Women with PCOS had higher triglycerides and lower HDL-C compared to women without PCOS. There was no evidence that evaluated polymorphisms influenced hepatic steatosis in women with and without PCOS. Conclusions: PCOS is not an independent factor influencing NAFLD in women. The influences on NAFLD incidence in women are BMI > 25 kg/m², glucose level > 80 mg/dL, E2/T < 80 and ALT > 19 IU/L as independent factors. Hyperandrogenism in PCOS may increase the risk of NAFLD indirectly by obesity, insulin resistance, and directly by the hepatotoxic effect. Polymorphisms rs328 and rs268 of the lipoprotein lipase gene do not affect the occurrence of NAFLD in women with PCOS or without PCOS. (Endokrynol Pol 2014; 65 (6): 416-421)

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Section: Introductionmentioning

confidence: 99%

Niealkoholowe stłuszczenie wątroby u kobiet z zespołem wielotorbielowatych jajników — aspekty kliniczne i metaboliczne oraz polimorfizm genu lipazy lipoproteinowej

Bohdanowicz-Pawlak

Lenarcik-Kabza

Brona

et al. 2015

Endokrynologia Polska

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“…Several polymorphisms have now been described in the LIPC gene, including a number of mutations associated with the rare HL deficiency condition (5,7,8,(13)(14)(15). Recent studies demonstrated that polymorphisms in the promoter of the LIPC gene are related to variants in plasma HDL-C concentrations, and the associations between LIPC gene promoter variants and HL activity have been reported (16)(17)(18)(19)(20)(21)(22)(23)(24).…”

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confidence: 99%

A novel allele in the promoter of the hepatic lipase is associated with increased concentration of HDL-C and decreased promoter activity

Zhang

Nebert

et al. 2002

Journal of Lipid Research

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Hepatic lipase (HL) is a lipolytic enzyme involved in the metabolism of plasma lipoproteins, especiallyHDLs. Association of the polymorphisms in the promoter region of the LIPC gene to post-heparin plasma HL activity and the plasma HDL-C concentration has been investigated thoroughly, but to date little is known about this in the Chinese. In the present study, we analyzed the polymorphisms in the promoter region of LIPC gene in Chinese patients with coronary artery disease (CAD) using denaturing high performance liquid chromatography (DHPLC) and DNA sequencing. As the result, a novel single nucleotide polymorphism ؊ 586T-to-C was identified and no linkage of this variant with other polymorphisms in the promoter was found. Compared with the nonsymptomatic control subjects, excess of carriers of the ؊ 586T/C substitution were detected in the CAD patients (43% vs. 31%, 2 ‫؍‬ 4.597, degree of freedom ‫؍‬ 2, P ‫؍‬ 0.032).The -586C allele carriers in the CAD patients had a significantly higher HDL-C level than the noncarriers (1.13 ؎ 0.24 mmol/l vs. 0.91 ؎ 0.14 mmol/l, P Ͻ 0.05). To test the functionality of this substitution, luciferase-reporter assays was performed in HepG2 cells. Promoter activity of the ؊ 586C construct was decreased 2-fold than the ؊ 586T construct.Our studies suggest that a T-to-C substitution at ؊ 586 of the LIPC promoter is associated with a lowered HL activity and that this variation may contribute to the increased plasma HDL-C concentration in the Chinese.

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“…The only report of linkage between LIPC and TG was a sib pair analysis in FCHL families (P Ͻ 0.026), in which linkage was also observed to LDL size (P Ͻ 0.019) and HDL cholesterol (P Ͻ 0.003) (66). In another sample of FCHL families, an LIPC polymorphism was associated with both dyslipidemia and insulin resistance (67). Additional genomic studies will be needed to determine whether the chromosome 15 linkage reported here is attributable to the LIPC gene.…”

Section: Discussionmentioning

confidence: 84%

Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia

Austin

Edwards

Monks

et al. 2003

Journal of Lipid Research

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Small, dense LDLs and hypertriglyceridemia, two highly correlated and genetically influenced risk factors, are known to predict for risk of coronary heart disease. The objective of this study was to perform a whole-genome scan for linkage to LDL size and triglyceride (TG) levels in 26 kindreds with familial hypertriglyceridemia (FHTG). LDL size was estimated using gradient gel electrophoresis, and genotyping was performed for 355 autosomal markers with an average heterozygosity of 76% and an average spacing of 10.2 centimorgans (cMs). Using variance components linkage analysis, one possible linkage was found for LDL size [logarithm of odds (LOD) ‫؍‬ 2.1] on chromosome 6, peak at 140 cM distal to marker F13A1 (closest marker D6S2436). With adjustment for TG and/or HDL cholesterol, the LOD scores were reduced, but remained in exactly the same location. For TG, LOD scores of 2.56 and 2.44 were observed at two locations on chromosome 15, with peaks at 29 and 61 cM distal to marker D15S822 (closest markers D15S643 and D15S211, respectively). These peaks were retained with adjustment for LDL size and/or HDL cholesterol. These findings, if confirmed, suggest that LDL particle size and plasma TG levels could be caused by two different genetic loci in FHTG. The causal relationship between LDL cholesterol and risk of coronary heart disease (CHD) is definitively established (1). But growing evidence reveals that other lipoproteins, including small, dense LDL particles, as well as increased plasma triglycerides (TGs) and lower HDL cholesterol levels, all characteristics of the metabolic syndrome (2), are also convincingly associated with atherosclerosis risk. Although these risk factors are all intercorrelated (3, 4), each of them is also an independent risk factor. For example, a meta-analysis of three prospective studies in middle-aged men (4-6) showed a 60% increased risk for CHD for every 10 Å decrease in LDL size (7). Adjustment for TG and HDL cholesterol reduced this to a 30% increased risk, but the odds ratio remained statistically significant, demonstrating that small LDL is an independent risk factor. Other studies have found even higher risk associated with CHD among young women (8), but lower risks among older populations (9, 10).Elevated plasma TG is now also recognized as an important independent risk factor for CHD (11)(12)(13)(14). In familial hypertriglyceridemia (FHTG), baseline TG levels predicted increased risk of cardiovascular disease mortality among first-degree relatives of probands during 20 years of follow-up, independent of baseline cholesterol levels and other covariates (15). Even more convincing data demonstrate that increasing HDL cholesterol levels can reduce risk of CHD among men with low HDL cholesterol levels (16,17).Numerous studies have demonstrated both genetic and environmental influences on LDL size, plasma TG, and HDL cholesterol (18,19). For example, segregation analyses (20, 21) have consistently demonstrated single major gene effects on LDL size. These and other studies h...

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G-250A Substitution in Promoter of Hepatic Lipase Gene Is Associated With Dyslipidemia and Insulin Resistance in Healthy Control Subjects and in Members of Families With Familial Combined Hyperlipidemia

Cited by 65 publications

References 64 publications

Niealkoholowe stłuszczenie wątroby u kobiet z zespołem wielotorbielowatych jajników — aspekty kliniczne i metaboliczne oraz polimorfizm genu lipazy lipoproteinowej

Niealkoholowe stłuszczenie wątroby u kobiet z zespołem wielotorbielowatych jajników — aspekty kliniczne i metaboliczne oraz polimorfizm genu lipazy lipoproteinowej

A novel allele in the promoter of the hepatic lipase is associated with increased concentration of HDL-C and decreased promoter activity

Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia

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