Genetic analysis of a polymorphism in the human apoA-V gene: effect on plasma lipids

Abstract

Recent discovery and characterization of APOAV suggests a role in metabolism of triglyceride (TG)-rich lipoproteins. Previously, variation at the APOAV locus was shown to modestly influence plasma TGs in normolipidemic samples. The aims of this study were to assess the effects of a polymorphism in APOAV (T-1131C) in terms of its frequency among three dyslipidemic populations and a control population, differences of allele frequency across available ethnic groups, and associations with specific lipoprotein TG and cholesterol compartments. We found a striking elevation in the frequency of the rare allele in a Chinese population (P = 0.0002) compared with Hispanic and European populations. The rare allele of the polymorphism was associated with elevated plasma TG (P = 0.012), VLDL cholesterol (P = 0.0007), and VLDL TG (P = 0.012), LDL TG (P = 0.003), and HDL TG (P = 0.016). Linear regression models predict that possession of the rare allele elevates plasma TG by 21 mg/dl (P = 0.009) and VLDL cholesterol by 8 mg/dl (P = 0.0001), and reduces HDL cholesterol by 2 mg/dl (P = 0.017). The association of the polymorphism with altered lipoprotein profiles was observed in combined hyperlipidemia, hypoalphalipoproteinemia, and hyperalphalipoproteinemia, and in controls.These findings indicate that APOAV is an important determinant of plasma TG and lipoprotein cholesterol, and is potentially a risk factor for cardiovascular disease. Recent discovery and characterization of APOAV suggests a role in metabolism of triglyceride (TG)-rich lipoproteins. Previously, variation at the APOAV locus was shown to modestly influence plasma TGs in normolipidemic samples. The aims of this study were to assess the effects of a polymorphism in APOAV (T-1131C) in terms of its frequency among three dyslipidemic populations and a control population, differences of allele frequency across available ethnic groups, and associations with specific lipoprotein TG and cholesterol compartments. We found a striking elevation in the frequency of the rare allele in a Chinese population (P = 0.0002) compared with Hispanic and European populations. The rare allele of the polymorphism was associated with elevated plasma TG (P = 0.012), VLDL cholesterol (P = 0.0007), and VLDL TG (P = 0.012), LDL TG (P = 0.003), and HDL TG (P = 0.016). Linear regression models predict that possession of the rare allele elevates plasma TG by 21 mg/dl (P = 0.009) and VLDL cholesterol by 8 mg/dl (P = 0.0001), and reduces HDL cholesterol by 2 mg/dl (P = 0.017). The association of the polymorphism with altered lipoprotein profiles was observed in combined hyperlipidemia, hypoalphalipoproteinemia, and hyperalphalipoproteinemia, and in controls. These findings indicate that APOAV is an important determinant of plasma TG and lipoprotein cholesterol, and is potentially a risk factor for cardiovascular disease. Atherosclerosis is the leading cause of morbidity and mortality in both industrialized and developing countries (1Genest Jr., J. McNamara J.R. Ordovas J.M. Jenner J.L. Silberman S.R. Anderson K.M. Wilson P.W. Salem D.N. Schaefer E.J. Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease.J. Am. Coll. Cardiol. 1992; 19: 792-802Google Scholar). The etiology of coronary artery disease is multifactorial, with both genetic and environmental determinants (2Davignon J. Genest Jr., J. Genetics of lipoprotein disorders.Endocrinol. Metab. Clin. North Am. 1998; 27: 521-550Google Scholar, 3Lusis A.J. Atherosclerosis.Nature. 2000; 407: 233-241Google Scholar). Abnormalities of lipoprotein metabolism are central to the development of atherosclerosis (4Farmer J.A. Gotto Jr., A.M. Dyslipidemia and the vulnerable plaque.Prog. Cardiovasc. Dis. 2002; 44: 415-428Google Scholar, 5Wilson P.W. Castelli W.P. Kannel W.B. Coronary risk prediction in adults (the Framingham Heart Study).Am. J. Cardiol. 1987; 59: 91G-94GGoogle Scholar). Study of premature coronary artery disease has revealed that apolipoproteins are important discriminating factors for distinguishing individuals with coronary artery disease (6McNamara J.R. Campos H. Ordovas J.M. Peterson J. Wilson P.W. Schaefer E.J. Effect of gender, age, and lipid status on low density lipoprotein subfraction distribution. Results from the Framingham Offspring Study.Arteriosclerosis. 1987; 7: 483-490Google Scholar, 7Rosseneu M. Fruchart J.C. Bard J.M. Nicaud V. Vinaimont N. Cambien F. De Backer G. Plasma apolipoprotein concentrations in young adults with a parental history of premature coronary heart disease and in control subjects. The EARS Study. European Atherosclerosis Research Study.Circulation. 1994; 89: 1967-1973Google Scholar, 8Genest J.J. McNamara J.R. Salem D.N. Schaefer E.J. Prevalence of risk factors in men with premature coronary artery disease.Am. J. Cardiol. 1991; 67: 1185-1189Google Scholar). The apolipoprotein gene cluster (APOAI-CIII-AIV) on human chromosome 11q23 is known to harbor at least three genes that affect the metabolism of plasma lipoproteins (9Groenendijk M. Cantor R.M. de Bruin T.W. Dallinga-Thie G.M. The apoAI-CIII-AIV gene cluster.Atherosclerosis. 2001; 157: 1-11Google Scholar). The relationship between variations in the gene cluster and plasma lipids has been studied for nearly two decades (9Groenendijk M. Cantor R.M. de Bruin T.W. Dallinga-Thie G.M. The apoAI-CIII-AIV gene cluster.Atherosclerosis. 2001; 157: 1-11Google Scholar, 10Aouizerat B.E. Allayee H. Bodnar J. Krass K.L. Peltonen L. de Bruin T.W. Rotter J.I. Lusis A.J. Novel genes for familial combined hyperlipidemia.Curr. Opin. Lipidol. 1999; 10: 113-122Google Scholar, 11Karathanasis S.K. Ferris E. Haddad I.A. DNA inversion within the apolipoproteins AI/CIII/AIV-encoding gene cluster of certain patients with premature atherosclerosis.Proc. Natl. Acad. Sci. USA. 1987; 84: 7198-7202Google Scholar, 12Ferns G.A. Galton D.J. Haplotypes of the human apoprotein AI-CIII-AIV gene cluster in coronary atherosclerosis.Hum. Genet. 1986; 73: 245-249Google Scholar). The majority of studies have focused on either apolipoprotein A-I (apoA-I), because of its influence on HDL production, or on apoC-III for its modulation of plasma triglyceride (TG). Recently, study of apoA-IV, an apolipoprotein associated with chylomicron and HDL particles (13Weinberg R.B. Spector M.S. Human apolipoprotein A-IV: displacement from the surface of triglyceride-rich particles by HDL2-associated C-apoproteins.J. Lipid Res. 1985; 26: 26-37Google Scholar), has provided evidence for its role in postprandial lipemia (14Hockey K.J. Anderson R.A. Cook V.R. Hantgan R.R. Weinberg R.B. Effect of the apolipoprotein A-IV Q360H polymorphism on postprandial plasma triglyceride clearance.J. Lipid Res. 2001; 42: 211-217Google Scholar) and coronary artery disease (15Kronenberg F. Stuhlinger M. Trenkwalder E. Geethanjali F.S. Pachinger O. von Eckardstein A. Dieplinger H. Low apolipoprotein A-IV plasma concentrations in men with coronary artery disease.J. Am. Coll. Cardiol. 2000; 36: 751-757Google Scholar). While variations in the APOAI-CIII-AIV gene cluster have been reported to influence several dyslipidemic states (16Aouizerat B.E. Allayee H. Cantor R.M. Dallinga-Thie G.M. Lanning C.D. de Bruin T.W. Lusis A.J. Rotter J.I. Linkage of a candidate gene locus to familial combined hyperlipidemia: lecithin:cholesterol acyltransferase on 16q.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2730-2736Google Scholar, 17Allayee H. Aouizerat B.E. Cantor R.M. Dallinga-Thie G.M. Krauss R.M. Lanning C.D. Rotter J.I. Lusis A.J. de Bruin T.W. Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype.Am. J. Hum. Genet. 1998; 63: 577-585Google Scholar, 18Dallinga-Thie G.M. van Linde-Sibenius Trip M. Rotter J.I. Cantor R.M. Bu X. Lusis A.J. de Bruin T.W. Complex genetic contribution of the Apo AI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes.J. Clin. Invest. 1997; 99: 953-961Google Scholar, 19Surguchov A.P. Page G.P. Smith L. Patsch W. Boerwinkle E. Polymorphic markers in apolipoprotein C-III gene flanking regions and hypertriglyceridemia.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 941-947Google Scholar, 20Rotter J.I. Bu X. Cantor R.M. Warden C.H. Brown J. Gray R.J. Blanche P.J. Krauss R.M. Lusis A.J. Multilocus genetic determinants of LDL particle size in coronary artery disease families.Am. J. Hum. Genet. 1996; 58: 585-594Google Scholar), the recent characterization of the proximal apoA-V provides evidence for a significant role in the modulation of levels of lipids and lipoproteins (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). The apoA-V gene (APOAV) was recently discovered by comparative sequencing of the APOAI-CIII-AIV gene region (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). Pennacchio and colleagues, by construction of both knockout and human transgenic murine models for apoA-V, established its role in modulating plasma TG, a major risk factor for coronary artery disease (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). Employing four single-nucleotide polymorphisms (SNPs) revealed during sequence analysis, significant associations were found between both plasma TG and VLDL in two human studies (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). The allele of of three in was associated with plasma TG among individuals for the major was association with a genetic in the apoC-III is known to plasma TG (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). indicate that APOAV polymorphisms important for susceptibility to recent of plasma TG, associated with an APOAV polymorphism in two suggests that APOAV to certain dyslipidemic states (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). variations in APOAV have in different ethnic to assess the frequency of the polymorphism in APOAV in three dyslipidemic and a control We for variations in allele frequency in three ethnic The of this variation on lipoprotein and was significant in allele frequency was in Chinese in with Hispanic and European populations. association with of the three dyslipidemic the APOAV allele was associated with elevated plasma TG, VLDL TG, LDL TG, and HDL TG, elevated VLDL cholesterol, and HDL regression of lipid regression models of for plasma TG, VLDL cholesterol, and HDL cholesterol, on allele study was a of the of the APOAV among three dyslipidemic population were from the of in W. J.A. apolipoprotein Identification of a that LDL Clin. Invest. Scholar), a study of heart the individuals with the combined hyperlipidemia plasma cholesterol plasma TG LDL cholesterol and VLDL cholesterol individuals with were HDL cholesterol the for and The Prevalence Study. of and Human of Scholar) and TG and with HDL cholesterol The on Human Research the was from for DNA and plasma lipid were W. J.A. apolipoprotein Identification of a that LDL Clin. Invest. Scholar, The Prevalence Study. of and Human of Scholar). of significant between the three and (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar) to a the A. A. N. J. The single-nucleotide polymorphism are a in 2001; Scholar). were to profiles with combined hyperlipidemia, hypoalphalipoproteinemia, or hyperalphalipoproteinemia, for at the APOAV provided an and population for and lipoprotein were patients for at least and were available on = were to of lipid and were because or the individuals were because were or that affect lipid at the of lipid a on cholesterol mg/dl for the of cholesterol and were a of in the study models for the lipid a among for the APOAV The polymorphism was in the of effects of the age, gender, lipoprotein profiles of populations status were in this and was of status and frequency was a of status A.P. R.J. and coronary heart disease an in to and from the J. Metab. 1992; 16: Scholar). status was for individuals a of for a A.P. R.J. and coronary heart disease an in to and from the J. Metab. 1992; 16: Scholar). to the of cardiovascular disease was an either coronary The of was was a for of the and R.J. J.M. The and of lipoproteins in human Clin. Invest. Scholar). HDL cholesterol was of lipoproteins with and J. J.J. for of Scholar). and TG levels were in plasma and in lipoprotein by either L. and J. cholesterol and triglyceride on the in Scholar) or J.C. R.J. of coronary atherosclerosis during of familial with combined Scholar). LDL cholesterol was the of the of the LDL cholesterol HDL cholesterol and the plasma HDL were provided by the for DNA was from from patients in the Lipid of W. J.A. apolipoprotein Identification of a that LDL Clin. Invest. Scholar). The or of the polymorphism of the (T-1131C) of the APOAV gene was (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar), was the were to a region of DNA by the The of the was to an in the of the in of was to the and at for The were on and and The for was and for regression and for regression models Scholar, and Scholar). regression models were by the on Scholar). of were a the of and Cox Cox D.R. An of Scholar). of were to the of the the among a was that effects and of the for levels of factors were effects with were on the were the N. Am. Scholar). of of the between factor are of a by the APOAV locus on plasma TG in two normolipidemic study of the of this locus in on the prediction that APOAV variation associated with in the TG and cholesterol of patients from the Lipid at and control J.A. apolipoprotein Identification of a that LDL Clin. Invest. Scholar) for an APOAV polymorphism associated with elevated TG (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). The of the four populations are in to elevated individuals with combined hyperlipidemia elevated VLDL TG, LDL TG, and HDL TG, and HDL with elevated VLDL cholesterol, LDL cholesterol, and the was with elevated VLDL cholesterol, LDL cholesterol, and of the study population for lipid for of or for of or for of or for of or for of or for of or for of or for of or for of or for of or for of or for of or for of or for of or for of or for of or 8 for of or for of or for of or for of or TG, are for lipoprotein are in to to for of or in a TG, are for lipoprotein are in to to the frequency for individuals the allele at was were to assess effects of population, gender, and Chinese = and = were compared with = of size population, gender, and were was with to three factors were with to and and population and within the European the of found significant differences in allele among the ethnic (P in the study significant (P = or effects (P = were with was for Chinese (P = 2 by ethnic for of the allele within the study frequency within major ethnic frequency within major ethnic in a the of population and within the European found significant in allele frequency between the four (P = were significant (P = or (P = effects of the that between the of was with to population (P = were significant with the control allele frequency population within the European and within the study frequency within within the European and in a the significant (P = the of allele frequency among population and was for the three for specific population control by the for individuals with was significant (P = the two the with the allele frequency for the for the effects of the polymorphism on lipoprotein significant in of TG and cholesterol and TG and cholesterol within and HDL were observed (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar), TGs were elevated in of the APOAV of the TG in the and HDL revealed that of the allele concentrations of lipids and in to APOAV size in size in in in Lipid in size in in a The was found to cholesterol levels in a that from this is to differences in the study populations. cholesterol was elevated in the VLDL (P = associated with in LDL in this of the allele a HDL cholesterol that (P = The association of the polymorphism with altered lipoprotein profiles was observed in combined hyperlipidemia, hypoalphalipoproteinemia, and hyperalphalipoproteinemia, in controls. models for lipid among the polymorphism and of the The of the age, gender, three of and the the and European ethnic groups, was and were for the or lipid effects were between population and and between population and of coronary disease or the effects of among controls. The models in a polymorphism are the or lipid a was found to for in the the was for LDL significant models were for or LDL the models that the polymorphism was lipid on the for and are in for plasma concentrations of to APOAV in in are for the on the Lipid in The are for the on the in a TG = the (P = effects population (P 0.0001), = 0.003), = = and = The 2 for the was VLDL cholesterol = the (P = population (P 0.0001), = = and = The 2 was HDL cholesterol = (P = was in the population (P 0.0001), = 0.0001), and The 2 was the for HDL cholesterol, the polymorphism was and combined (P = effects were with The 2 was for the study of APOAV variation revealed a influence on TG in normolipidemic the in dyslipidemic states was (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). We that a of associated with elevated plasma TG and VLDL in two populations and among specific dyslipidemic populations in to an control an frequency was observed in the combined hyperlipidemia control this is the recent of frequency of the rare allele in individuals with familial combined hyperlipidemia J. L. J. E. M. L. J. apolipoprotein gene to plasma triglycerides in familial combined 2002; the low frequency of the allele in the population in a of the allele in individuals J. L. J. E. M. L. J. apolipoprotein gene to plasma triglycerides in familial combined 2002; Scholar). evidence of association with either or was The different ethnic of the four populations to control for in the of allele this was to size that was to the European with countries of populations of to ethnic have levels of are for genetic variations to the contribution of APOAV to the etiology of dyslipidemic states across the of association within European populations is and in a population of genetic association Genet. 2001; Scholar). with the allele frequency established in a normolipidemic study population (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar), found an elevated frequency of The of with to lipoprotein in the of dyslipidemic individuals at the population the control population four individuals with combined hyperlipidemia, individuals with hypoalphalipoproteinemia, and three individuals with to a atherogenic lipoprotein an control population in elevated susceptibility allele compared with a normolipidemic of allele frequency in the of in lipoprotein metabolism and cardiovascular disease risk has been the of of differences in susceptibility of candidate genes gender, and the role of lipoprotein for J. Cardiol. 2000; Scholar, van van factors for coronary heart of Res. 2002; Scholar, R.A. of candidate genes in triglyceride Cardiovasc. 2000; 7: Scholar). the European striking differences in allele were observed between and allele frequency was elevated in both combined hyperlipidemia and the was observed in observed this the (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). both of the role of APOAV in lipoprotein the allele was associated with elevated plasma found evidence of TG in lipoprotein was the of a significant in VLDL cholesterol in of the in with the of VLDL TG in the the of VLDL in of the allele (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). The of HDL cholesterol in the elevated plasma TG to combined hyperlipidemia and an control population with to levels of HDL cholesterol enriched in of the allele to elevated TG risk factor for triglyceride-rich 2001; Scholar, J.L. Genetics of lipoprotein abnormalities associated with coronary artery disease Genet. 2000; Scholar). models for the lipid among of the allele of the major allele were in the of effects of the three of and risk factors for cardiovascular disease. models of on were available for TG, VLDL cholesterol, and HDL of the allele on a elevation in plasma is a elevation the to possession of the allele (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). the striking observed in of the allele is elevation in VLDL VLDL cholesterol is a of cholesterol, a of an atherogenic with in a H. M. association of cardiovascular risk factors with and 2000; Scholar, lipoprotein cholesterol risk and 2001; Scholar). The significant elevation of VLDL cholesterol observed to genetic variation at the APOAV locus its a The of individuals for the rare allele to two regression models for HDL three were the the were and the factor = the in a in HDL cholesterol (P = the for in a (P = is to the the several in the for states have profiles D.J. in from the Genet. 2001; Scholar, E. J. G. gene for of the variation in plasma Clin. Invest. 1992; Scholar), the least of is a of a across the APOAI-CIII-AIV gene cluster to G.A. Galton D.J. Haplotypes of the human apoprotein AI-CIII-AIV gene cluster in coronary atherosclerosis.Hum. Genet. 1986; 73: 245-249Google Scholar, 18Dallinga-Thie G.M. van Linde-Sibenius Trip M. Rotter J.I. Cantor R.M. Bu X. Lusis A.J. de Bruin T.W. Complex genetic contribution of the Apo AI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes.J. Clin. Invest. 1997; 99: 953-961Google Scholar). that from four of the gene cluster in to the of this locus to lipoprotein metabolism and cardiovascular risk M. De Bruin T.W. Dallinga-Thie G.M. polymorphisms in the A-IV gene and familial combined 2001; Scholar, M. Cantor R.M. H. Dallinga-Thie G.M. in the region are associated with familial combined J. Clin. Invest. 2001; Scholar, M. Cantor R.M. De Bruin T.W. Dallinga-Thie G.M. genetic in the and apoC-III genes and familial combined Lipid Res. 2001; 42: Scholar). of in the region of APOAV and the gene cluster revealed a of genetic determinants of TG L.A. Olivier M. Hubacek J.A. Krauss R.M. Rubin E.M. Cohen J.C. apolipoprotein influence human plasma triglyceride Genet. 2002; Scholar, P.J. E. Olivier M. Rubin E.M. Pennacchio L.A. contribution of variation within the gene cluster in plasma Genet. 2002; Scholar). a at of apoA-V was associated with modestly plasma TG in of the allele L.A. Olivier M. Hubacek J.A. Krauss R.M. Rubin E.M. Cohen J.C. apolipoprotein influence human plasma triglyceride Genet. 2002; Scholar). Recent of and APOAV has revealed that and have an on plasma TG P.J. E. Olivier M. Rubin E.M. Pennacchio L.A. contribution of variation within the gene cluster in plasma Genet. 2002; Scholar). both polymorphisms are in association with polymorphism in found to plasma TG P.J. E. Olivier M. Rubin E.M. Pennacchio L.A. contribution of variation within the gene cluster in plasma Genet. 2002; Scholar). of the APOAI-CIII-AIV gene cluster and APOAV within a study population the of both and polymorphisms on TG of ethnic differences in the study revealed a striking elevation of allele frequency in Chinese The of allele frequency among Chinese individuals was observed of was observed in size of allele frequency association of with elevated plasma TG and HDL cholesterol was reported in a study of H. J. found between the region polymorphism in the apolipoprotein gene and the triglyceride in Genet. 2002; Scholar). Study of populations a revealed an of coronary disease and to that observed in populations and coronary heart disease in J. Scholar, Plasma lipid profiles and of in Scholar, M. G.M. Plasma lipid and lipoprotein concentrations in Chinese with coronary artery with and 1987; 67: Scholar, of plasma lipids and markers for coronary artery disease in N. Acad. Sci. Scholar, J. coronary study on coronary artery size during J. Cardiol. Scholar). suggests that the role of APOAV in TG metabolism in populations has a significant on coronary disease and The role of the polymorphism is a recent was found to in with an L.A. Olivier M. Hubacek J.A. Krauss R.M. Rubin E.M. Cohen J.C. apolipoprotein influence human plasma triglyceride Genet. 2002; Scholar). While to the sequence for of that of the of both variations is L.A. Olivier M. Hubacek J.A. Krauss R.M. Rubin E.M. Cohen J.C. apolipoprotein influence human plasma triglyceride Genet. 2002; Scholar). evidence from of a of studies on a of patients established an of TG an risk factor for heart disease risk factor for triglyceride-rich 2001; Scholar, J.L. Genetics of lipoprotein abnormalities associated with coronary artery disease Genet. 2000; Scholar). The of lipoproteins in human provides evidence for a role in R.J. J. size of lipoproteins from human a Vasc. Scholar). the APOAV for and of cardiovascular disease have a significant modulation of the levels of this in human patients with VLDL levels VLDL and TG potentially HDL the atherogenic the risk of cardiovascular disease. The to the and for in this We and the of the Lipoprotein at The of for We to for The of in Genetics The and was by from and and