Paper - WANFANG MED ONLINE

You Position: Home > Paper

Linkage of the cholesterol 7α-hydroxylase gene and low-density lipoprotein cholesterol conditional on apolipoprotein E association: the National Heart, Lung, and Blood Institute Family Heart Study

( views:140, downloads:0 )

Author:: No author available

Journal Title:: CHINESE MEDICAL JOURNAL

Issue:: 5

DOI:: No doi available

Key Word:: linkage analysis;CYP7 gene;apoE gene;low-density lipoprotein cholesterol

Abstract： Background Genetic factors account for approximately 50% of the individual variation in plasma low-density lipoprotein cholesterol (LDL-C) concentrations in the general population. Several candidate genes have been proposed but their relative contributions to the variance in LDL-C are not known, except for apolipoprotein E (apoE). We report here an investigation of the relationship between LDL-C and cholesterol 7α-hydroxylase (CYP7), as well as apoE and low-density lipoprotein receptor (LDLR), three pivotal genes in LDL metabolism. Methods Our study population included more than 200 nuclear families with increased coronary heart disease (CHD) risk from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Variance-component linkage methods, a measured genotype approach, and a variance-component linkage analysis conditional on a measured genotype association were used. Results The results showed significant linkage between a genetic determinant of plasma LDL-C concentrations and a polymorphism near CYP7 with its allelic variation accounting for 27% of the total LDL-C variation. There is significant association between plasma LDL-C concentrations and apoE genotypes. Conditional on the apoE association, the total LDL-C variation accounted by allelic variation of a polymorphism near CYP7 was increased significantly.Conclusion Our results suggest the apoE and CYP7 may be two important genes accounting for the genetic variation of plasma LDL-C concentrations in a population with cardiovascular diseases.

Reference

[1]C K, Garcia,K, Wilund,M, Arca,etc.Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.[J].2001,292.
[2]Laird NM,Horvath S,Xu X.The family based association test method: strategies for studying general genotype--phenotype associations.[J].2001,9(4).
[3]W T, Friedewald,R I, Levy,D S, Fredrickson.Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.[J].1972,18.
[4]M, Higgins,M, Province,G, Heiss,etc.NHLBI Family Heart Study: objectives and design.[J].1996,143.
[5]Guerra R,Wang J,Grundy SM,etc.Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.[J].1998,101(6).
[6]Varret,M,Rabes,JP,Saint,Jore-B,etc.A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32.[J].1999,64(5).
[7]John Blangero,Laura Almasy.Multipoint oligogenic linkage analysis of quantitative traits[J].1997,14(6).
[8]J. L. HOPPER,J. D. MATHEWS.Extensions to multivariate normal models for pedigree analysis[J].1982,46(4).
[9]Hanefeld M,Tiebel M,Paetzold A,etc.Mutations of the human hepatic lipase gene in patients with combined hypertriglyceridemia/hyperalphalipoproteinemia and in patients with familial combined hyperlipidemia.[J].1999,77(10).
[10]R C, Kowal,J, Herz,K H, Weisgraber,etc.Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein.[J].1990,265.
[11]N J, Risch,H, Zhang.Mapping quantitative trait loci with extreme discordant sib pairs: sampling considerations.[J].1996,58.
[12]P, de Knijff,A M, van den Maagdenberg,R R, Frants,etc.Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels.[J].1994,4(3).
[13]Comuzzie,AG,Williams,JT.Correcting for ascertainment bias in the COGA data set.[J].1999,17(Suppl 1).
[14]S C, Hunt,P N, Hopkins,K, Bulka,etc.Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred.[J].2000,20.
[15]Meidell RS,Spady DK,Cuthbert JA,etc.Overexpression of cholesterol 7alpha-hydroxylase (CYP7A) in mice lacking the low density lipoprotein (LDL) receptor gene. LDL transport and plasma LDL concentrations are reduced.[J].1998,273(1).
[16]Laura Almasy,John Blangero.Multipoint Quantitative-Trait Linkage Analysis in General Pedigrees[J].1998,62(5).
[17]Knoblauch,H,Muller,Myhsok-B,Busjahn,A,etc.A cholesterol-lowering gene maps to chromosome 13q.[J].2000,66(1).
[18]K. D. Bucher,Y. Friedlander,E. B. Kaplan,etc.Biological and cultural sources of familial resemblance in plasma lipids: A comparison between North America and Israel-the lipid research clinics program[J].1988,5(1).
[19]Cupples LA,Couture P,Schaefer EJ,etc.Association of the A-204C polymorphism in the cholesterol 7alpha-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study.[J].1999,40(10).
[20]Province MA,Arnett DK,Williams RR,etc.Evidence for a major gene accounting for mild elevation in LDL cholesterol: the NHLBI Family Heart Study.[J].1999,63(Pt.5).
[21]V I, Zannis,P W, Just,J L, Breslow.Human apolipoprotein E isoprotein subclasses are genetically determined.[J].1981,33.
[22]Groenendijk M,De-Bruin TW,Dallinga-Thie GM,etc.New genetic variants in the apoA-I and apoC-III genes and familial combined hyperlipidemia.[J].2001,42(2).
[23]North BV,Curtis D,Sham PC.A novel method of two-locus linkage analysis applied to a genome scan for late onset Alzheimer's disease.[J].2001,65(Pt.5).
[24]V I, Zannis,J L, Breslow.Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification.[J].1981,20(4).
[25]E, Reihnér,B, Angelin,M, Rudling,etc.Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients.[J].1990,31.
[26]Ehnholm C.,Peltonen L.,Ylitalo K. Pihlajamaki J.,etc.Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23[J].1998,18(4).
[27]Spady DK,Cuthbert JA,Willard MN,etc.Adenovirus-mediated transfer of a gene encoding cholesterol 7 alpha-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol.[J].1995,96(2).
[28]Adamson D.,Ballard L.,Bradley P.,etc.A Collection of Ordered Tetranucleotide-Repeat Markers from the Human Genome[J].1995,57(3).
[29]T, Rice,G P, Vogler,T S, Perry,etc.Familial aggregation of lipids and lipoproteins in families ascertained through random and nonrandom probands in the Iowa Lipid Research Clinics family study.[J].1991,41.