Polymorphisms in the hepatic lipase gene affect plasma HDL-cholesterol levels in a Turkish population

Hodoğlugil, Uğur; Williamson, David; Mahley, Robert W.

doi:10.1194/jlr.p001578

Cited by 36 publications

(37 citation statements)

References 57 publications

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“…Mutations in the LIPC gene may have a direct effect on HL function, or may indirectly affect lipolysis by causing reduced or dysfunctional HDL particles. 7,8,10 Stimulants of hepatic HDL production may therefore act through cofactor pathways to stimulate lipolytic enzymes and enhance TG clearance. 43 This may in part explain why drugs that increase HDL levels, such as the fibrates and niacin, also reduce plasma TG levels.…”

Section: Resultsmentioning

confidence: 99%

“…SNPs in the LIPC gene can be associated with both increased or decreased plasma levels of HDL cholesterol and with varied levels of CHD risk. 7,8 Thus, unique SNPs may consequently confer both pro-and anti-atherogenic phenotypic consequences. This may explain why larger and more comprehensive studies have not observed an association between LIPC mutations and CHD risk.…”

Section: Triglycerides and Heart Diseasementioning

confidence: 99%

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Hepatic Lipase, High Density Lipoproteins, and Hypertriglyceridemia

Chatterjee

Sparks

2011

The American Journal of Pathology

111

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Hepatic lipase (HL) is a lipolytic enzyme that contributes to the regulation of plasma triglyceride (TG) levels. Elevated TG levels may increase the risk of developing coronary heart disease, and studies suggest that mutations in the HL gene may be associated with elevated TG levels and increased risk of coronary heart disease. Hepatic lipase facilitates the clearance of TG from the very low density lipoprotein (VLDL) pool, and this function is governed by the composition and quality of high density lipoprotein (HDL) particles. In humans, HL is a liver resident enzyme regulated by factors that release it from the liver and activate it in the bloodstream. HDL regulates the release of HL from the liver and HDL structure controls HL transport and activation in the circulation. Alterations in HDL-apolipoprotein composition can perturb HL function by inhibiting the release and activation of the enzyme. HDL structure may therefore affect plasma TG levels and coronary heart disease risk. Triglycerides and Heart DiseaseElevated plasma triglyceride (TG) levels have been viewed as a risk factor for coronary heart disease (CHD) for more than a decade.1,2 Plasma TG levels are regulated by both synthesis and degradation of both very low density lipoprotein (VLDL) and chylomicron particles. The clearance of TG-rich lipoproteins from the circulation is controlled by the actions of lipoprotein lipase (LPL) and hepatic lipase (HL) and by the interlipoprotein exchange of TG by cholesteryl ester transfer protein. Lipoprotein lipase is the predominant TG lipase and is responsible for hydrolyzing TG in chylomicrons and VLDL, whereas HL is both a phospholipase and a TG lipase and plays an important role in HDL metabolism and in the conversion of VLDL to LDL.3 Single nucleotide polymorphisms (SNPs) in the HL gene (LIPC) have been shown to associate with plasma lipid concentrations and increased CHD risk. 4,5 Hepatic lipase deficiency is a result of relatively rare LIPC mutations that give rise to a loss in circulating HL activity (due to impaired secretion or inactive enzyme) and cause an increase in TG-rich HDL and VLDL remnants and increased CHD risk.

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Section: Resultsmentioning

confidence: 99%

Section: Triglycerides and Heart Diseasementioning

confidence: 99%

Hepatic Lipase, High Density Lipoproteins, and Hypertriglyceridemia

Chatterjee

Sparks

2011

The American Journal of Pathology

111

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“…Recent genome-wide SNP association studies and earlier candidate gene analysis revealed association of SNPs in the LIPC gene with HDL-C levels ( 14,27 ). Because LIPC is located within the small QTL for HDL-C on 15q22 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…These results are identical to those generated by a populationFor chromosome 15q25 QTL for HDL-C, fi ne mapping studies split the QTL into two separate QTLs, one major QTL on 15q25 with a maximum LOD score of 5.63 and the other minor QTL on 15q22 that showed a maximum LOD score of 2.73 and covered the LPIC gene. Two SNPs, including rs1491579 and rs11638634 close to marker D15S655 showing the maximum LOD score, were analyzed for association with HDL-C, but no based association study reported in a Turkish population ( 27 ). To the best of our knowledge, this is the fi rst family-based QTDT study to demonstrate the association between LIPC and HDL-C. On the other hand, the specifi c gene responsible for the major 15q25 HDL-C QTL remains to be identifi ed.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide linkage scan identifies multiple quantitative trait loci for HDL-cholesterol levels in families with premature CAD and MI

Yang

Seidelmann

et al. 2010

Journal of Lipid Research

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Coronary artery disease (CAD) and its principal clinical complication of acute myocardial infarction (MI) represent the most important causes of death and disability in the developed world. According to the American Heart Association's 2009 statistical update, nearly 16.8 million Americans are affected with CAD, and 7.9 million have had a myocardial infarction. On average, an American will suffer from a coronary event every 26 s, and about every minute somebody will die from one ( 1 ). The lifetime risk of developing CAD after age 40 is 49% for men and 32% for women ( 1 ).A decreased concentration of plasma HDL-cholesterol (HDL-C) is a major risk factor for CAD, and epidemiological evidence from several longitudinal studies, including the Framingham Heart Study, indicate that HDL-C is an Abstract Plasma HDL cholesterol levels (HDL-C) are an independent predictor of coronary artery disease (CAD). We have completed a genome-wide linkage scan for HDL-C in a US cohort consisting of 388 multiplex families with premature CAD (GeneQuest). The heritability of HDL-C in GeneQuest was 0.37 with gender and age as covariates ( P = 5.1 × 10 ؊ 4 ). Two major quantitative trait loci (QTL) for logtransformed HDL-C adjusted for age and gender were identifi ed onto chromosomes 7p22 and 15q25 with maximum multipoint logarithm of odds (LOD) scores of 3.76 and 6.69, respectively. Fine mapping decreased the 7p22 LOD score to a nonsignifi cant level of 3.09 and split the 15q25 QTL into two loci, one minor QTL on 15q22 (LOD = 2.73) that spanned the LIPC gene, and the other at 15q25 (LOD = 5.63). A family-based quantitative transmission disequilibrium test (QTDT) revealed signifi cant association between variant rs1800588 in LIPC and HDL-C in the GeneQuest population ( P = 0.0067), which may account for the minor QTL on 15q22. The 15q25 QTL is the most signifi cant locus identifi ed for HDL-C to date, and these results provide a framework for the ultimate identifi cation of the underlying HDL-C variant and gene on chromosomes 15q25, which will provide insights into novel regulatory mechanisms of HDL-C metabolism.

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“…7,8 Different groups examined several genes associated with low HDL-C levels in the Turkish population, including cholesteryl ester transfer protein, ATP binding cassette transporter A1 (ABCA-1), and hepatic lipase (LIPC) gene. [9][10][11] Five LIPC single nucleotide polymorphisms (SNPs: rs4775041, rs1800588, rs11858164, rs11856322, and rs2242061), cholesteryl ester transfer protein I405V, and Taq IB polymorphisms associate with low HDL-C levels among the Turkish population. [9][10][11] Lecithin:cholesterol acyltransferase (LCAT) is one of the key enzymes that controls cholesterol homeostasis and transport and has a pivotal role in HDL-C maturation and remodeling.…”

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confidence: 99%