Abstract
The objective of this paper was to identify the single nucleotide polymorphisms (SNPs) that show unshared effects on plasma triglyceride (TG) levels and to investigate whether these SNPs show statistically independent effects on plasma TG levels. In total, 59 polymorphisms in 20 genes involved in lipid metabolism were investigated. Polymorphisms were selected for a multivariate ANOVA model if they showed an univariate association with TG (after adjustment for HDL-C and LDL-C) in more than 50% of bootstrap samples that were made from the original data. The multivariate model included 512 men with coronary artery disease from the REGRESS study who were completely genotyped for eight polymorphisms selected in the univariate procedure (ie, APOA1 G(−75)A, ABCA1 C(−477)T, ABCA1 G1051A, APOC3 T3206G, APOE Arg158Cys, LIPC C(−514)T, LPL Asn291Ser and LPL Ser447Stop). The gene variants APOA1 G(−75)A (P=0.04) and LPL Asn291Ser (P=0.03) were significantly associated with plasma TG levels in this multivariate analysis. The eight polymorphisms explained 8.9% of the variation in plasma TG levels. In conclusion, this study showed statistically independent effects of gene variants in the APOA1 and LPL genes on fasting plasma levels of TG. Nevertheless, only a small part of variation in TG levels could be explained by the polymorphisms.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Cullen P : Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol 2000; 86: 943–949.
Gurr MI : Fats; in Garrow JS, James WPT, Ralph A (eds): Human nutrition and dietetics. Edinburgh: Churchill Livingstone, 2000, pp 97–120.
Mead JR, Irvine SA, Ramji DP : Lipoprotein lipase: structure, function, regulation, and role in disease. J Mol Med 2002; 80: 753–769.
Attie AD, Kastelein JP, Hayden MR : Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis. J Lipid Res 2001; 42: 1717–1726.
Oram JF, Lawn RM : ABCA1. The gatekeeper for eliminating excess tissue cholesterol. J Lipid Res 2001; 42: 1173–1179.
Barter PJ, Brewer Jr HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR : Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol 2003; 23: 160–167.
Snieder H, van Doornen LJ, Boomsma DI : Dissecting the genetic architecture of lipids, lipoproteins, and apolipoproteins: lessons from twin studies. Arterioscler Thromb Vasc Biol 1999; 19: 2826–2834.
Wittrup HH, Tybjaerg-Hansen A, Nordestgaard BG : Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis. Circulation 1999; 99: 2901–2907.
Talmud PJ, Hawe E, Martin S et al: Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Hum Mol Genet 2002; 11: 3039–3046.
Kastelein JJ, Ordovas JM, Wittekoek ME et al: Two common mutations (D9N, N291S) in lipoprotein lipase: a cumulative analysis of their influence on plasma lipids and lipoproteins in men and women. Clin Genet 1999; 56: 297–305.
Arya R, Duggirala R, Williams JT, Almasy L, Blangero J : Power to localize the major gene for disease liability is increased after accounting for the effects of related quantitative phenotypes. Genet Epidemiol 2001; 21 (Suppl 1): S774–S778.
Hauser ER, Hsu FC, Daley D et al: Effects of covariates: a summary of Group 5 contributions. Genet Epidemiol 2003; 25 (Suppl 1): S43–S49.
Draper NR, Smith H : Applied regression analysis. New York: John Wiley & Sons, 1981.
Jukema JW, Bruschke AV, van Boven AJ et al: Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91: 2528–2540.
Cheng S, Grow MA, Pallaud C et al: A multilocus genotyping assay for candidate markers of cardiovascular disease risk. Genome Res 1999; 9: 936–949.
Pennacchio LA, Olivier M, Hubacek JA et al: An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science 2001; 294: 169–173.
Clee SM, Zwinderman AH, Engert JC et al: Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease. Circulation 2001; 103: 1198–1205.
Zwarts KY, Clee SM, Zwinderman AH et al: ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels. Clin Genet 2002; 61: 115–125.
Klerkx AH, Tanck MW, Kastelein JJ et al: Haplotype analysis of the CETP gene: not TaqIB, but the closely linked −629C → A polymorphism and a novel promoter variant are independently associated with CETP concentration. Hum Mol Genet 2003; 12: 111–123.
Jansen H, Verhoeven AJ, Weeks L et al: Common C-to-T substitution at position −480 of the hepatic lipase promoter associated with a lowered lipase activity in coronary artery disease patients. Arterioscler Thromb Vasc Biol 1997; 17: 2837–2842.
Flavell DM, Pineda TI, Jamshidi Y et al: Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects. Diabetologia 2000; 43: 673–680.
Lutucuta S, Ballantyne CM, Elghannam H, Gotto Jr AM, Marian AJ : Novel polymorphisms in promoter region of ATP binding cassette transporter gene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy. Circ Res 2001; 88: 969–973.
Stocks J, Cooke CJ, Miller NE : A common lecithin: cholesterol acyltransferase gene variant (Ser208 → Thr). Atherosclerosis 2000; 149: 219–220.
Kamboh MI, Aston CE, Nestlerode CM, McAllister AE, Hamman RF : Haplotype analysis of two APOA1/MspI polymorphisms in relation to plasma levels of apo A-I and HDL-cholesterol. Atherosclerosis 1996; 127: 255–262.
Guerra R, Wang J, Grundy SM, Cohen JC : A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol. Proc Natl Acad Sci USA 1997; 94: 4532–4537.
Acton S, Osgood D, Donoghue M et al: Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and body mass index in a white population. Arterioscler Thromb Vasc Biol 1999; 19: 1734–1743.
Leus FR, Zwart M, Kastelein JJ, Voorbij HA : PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients. Atherosclerosis 2001; 154: 641–649.
Karpe F, Lundahl B, Ehrenborg E, Eriksson P, Hamsten A : A common functional polymorphism in the promoter region of the microsomal triglyceride transfer protein gene influences plasma LDL levels. Arterioscler Thromb Vasc Biol 1998; 18: 756–761.
Peacock RE, Hamsten A, Nilsson-Ehle P, Humphries SE : Associations between lipoprotein lipase gene polymorphisms and plasma correlations of lipids, lipoproteins and lipase activities in young myocardial infarction survivors and age-matched healthy individuals from Sweden. Atherosclerosis 1992; 97: 171–185.
Miserez AR, Schuster H, Chiodetti N, Keller U : Polymorphic haplotypes and recombination rates at the LDL receptor gene locus in subjects with and without familial hypercholesterolemia who are from different populations. Am J Hum Genet 1993; 52: 808–826.
Kuivenhoven JA, de Knijff P, Boer JM et al: Heterogeneity at the CETP gene locus. Influence on plasma CETP concentrations and HDL cholesterol levels. Arterioscler Thromb Vasc Biol 1997; 17: 560–568.
Hobbs HH, Esser V, Russell DW : AvaII polymorphism in the human LDL receptor gene. Nucleic Acids Res 1987; 15: 379.
Hoh J, Wille A, Zee R et al: Selecting SNPs in two-stage analysis of disease association data: a model-free approach. Ann Hum Genet 2000; 64: 413–417.
Pritchard JK, Stephens M, Donnelly P : Inference of population structure using multilocus genotype data. Genetics 2000; 155: 945–959.
Xu CF, Talmud P, Schuster H, Houlston R, Miller G, Humphries S : Association between genetic variation at the APO AI-CIII-AIV gene cluster and familial combined hyperlipidaemia. Clin Genet 1994; 46: 385–397.
Larson IA, Ordovas JM, Barnard JR et al: Effects of apolipoprotein A-I genetic variations on plasma apolipoprotein, serum lipoprotein and glucose levels. Clin Genet 2002; 61: 176–184.
Kamboh MI, Bunker CH, Aston CE, Nestlerode CS, McAllister AE, Ukoli FA : Genetic association of five apolipoprotein polymorphisms with serum lipoprotein–lipid levels in African blacks. Genet Epidemiol 1999; 16: 205–222.
Yamamoto M, Morita SY, Kumon M et al: Effects of plasma apolipoproteins on lipoprotein lipase-mediated lipolysis of small and large lipid emulsions. Biochim Biophys Acta 2003; 1632: 31–39.
Danek GM, Valenti M, Baralle FE, Romano M : The A/G polymorphism in the −78 position of the apolipoprotein A-I promoter does not have a direct effect on transcriptional efficiency. Biochim Biophys Acta 1998; 1398: 67–74.
Angotti E, Mele E, Costanzo F, Avvedimento EV : A polymorphism (G → A transition) in the −78 position of the apolipoprotein A-I promoter increases transcription efficiency. J Biol Chem 1994; 269: 17371–17374.
Juo SH, Wyszynski DF, Beaty TH, Huang HY, Bailey-Wilson JE : Mild association between the A/G polymorphism in the promoter of the apolipoprotein A-I gene and apolipoprotein A-I levels: a meta-analysis. Am J Med Genet 1999; 82: 235–241.
Arca M, Campagna F, Montali A et al: The common mutations in the lipoprotein lipase gene in Italy: effects on plasma lipids and angiographically assessed coronary atherosclerosis. Clin Genet 2000; 58: 369–374.
Fisher RM, Mailly F, Peacock RE et al: Interaction of the lipoprotein lipase asparagine 291 → serine mutation with body mass index determines elevated plasma triacylglycerol concentrations: a study in hyperlipidemic subjects, myocardial infarction survivors, and healthy adults. J Lipid Res 1995; 36: 2104–2112.
Razzaghi H, Aston CE, Hamman RF, Kamboh MI : Genetic screening of the lipoprotein lipase gene for mutations associated with high triglyceride/low HDL-cholesterol levels. Hum Genet 2000; 107: 257–267.
Ferencak G, Pasalic D, Grskovic B et al: Lipoprotein lipase gene polymorphisms in Croatian patients with coronary artery disease. Clin Chem Lab Med 2003; 41: 541–546.
Wittrup HH, Tybjaerg-Hansen A, Abildgaard S, Steffensen R, Schnohr P, Nordestgaard BG : A common substitution (Asn291Ser) in lipoprotein lipase is associated with increased risk of ischemic heart disease. J Clin Invest 1997; 99: 1606–1613.
Fisher RM, Humphries SE, Talmud PJ : Common variation in the lipoprotein lipase gene: effects on plasma lipids and risk of atherosclerosis. Atherosclerosis 1997; 135: 145–159.
Dallongeville J, Meirhaeghe A, Cottel D, Fruchart JC, Amouyel P, Helbecque N : Gender related association between genetic variations of APOC-III gene and lipid and lipoprotein variables in northern France. Atherosclerosis 2000; 150: 149–157.
Salah D, Bohnet K, Gueguen R, Siest G, Visvikis S : Combined effects of lipoprotein lipase and apolipoprotein E polymorphisms on lipid and lipoprotein levels in the Stanislas cohort. J Lipid Res 1997; 38: 904–912.
Acknowledgements
JW Jukema is an established clinical investigator of the Netherlands Heart Foundation (2001 D032), The Hague, the Netherlands and MWT Tanck was financially supported by the Netherlands Heart Foundation Grant No. 2000.125.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Souverein, O., Jukema, J., Boekholdt, S. et al. Polymorphisms in APOA1 and LPL genes are statistically independently associated with fasting TG in men with CAD. Eur J Hum Genet 13, 445–451 (2005). https://doi.org/10.1038/sj.ejhg.5201362
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5201362
Keywords
This article is cited by
-
Association of the S2 allele of the SstI polymorphism in the apoC3 gene with plasma apoCIII interacts with unfavorable lipid profiles to contribute to atherosclerosis in the Li ethnic group in China
Lipids in Health and Disease (2017)
-
Functional Variants of Lipid Level Modifier MLXIPL, GCKR, GALNT2, CILP2, ANGPTL3 and TRIB1 Genes in Healthy Roma and Hungarian Populations
Pathology & Oncology Research (2015)
-
Association of apolipoprotein A1 -75 G/A polymorphism with susceptibility to the development of acute lung injury after cardiopulmonary bypass surgery
Lipids in Health and Disease (2013)
-
Lipoprotein Lipase (A1127G) Gene Polymorphism: A Case–Control Association Study
Biochemical Genetics (2011)
-
Triglyceride Level-Influencing Functional Variants of the ANGPTL3, CILP2, and TRIB1 Loci in Ischemic Stroke
NeuroMolecular Medicine (2011)
