Abstract
There is an increasing interest to understand the molecular basis of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) subfractions and their association with coronary artery disease (CAD). The formation of these subfractions is greatly influenced by hepatic lipase (HL) and cholesteryl ester transfer protein (CETP) enzymes. To identify genetic markers influencing LDL and HDL subfractions and their role in CAD we performed a case–control genetic association study on 117 healthy controls and 119 angiographically verified CAD patients. Biochemical analysis was performed using standard assays. HDL-C and LDL-C subfractions were estimated using precipitation methods. Genotyping of C-514T (rs1800588) in the LIPC gene for HL and I405V (rs5882) in the CETP gene was done using PCR-based restriction enzyme analysis and sequencing. Both the polymorphisms were not associated with CAD. The C-514T was associated with increased HDL3-C levels in controls (P = 0.049). The I405V polymorphism was found to be associated with low levels of small dense, LDL (P = 0.038). A multiple regression analysis showed that the effects were dependent on gender and triglyceride levels. We conclude that these polymorphisms are not associated with CAD but are important determinants of HDL-C and small dense LDL particles in our population.
Similar content being viewed by others
References
Enas EA. Coronary artery disease epidemic in Indians: a cause for alarm and call for action. J Indian Med Assoc. 2000;98(11):694–702.
Krauss RM. Is the size of low-density lipoprotein particles related to the risk of coronary heart disease? J Am Med Assoc. 2002;287(6):712–3.
Salonen JT, Salonen R, Seppänen K, Rauramaa R, Tuomilehto J. HDL, HDL2 and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. Circulation. 1991;84(1):129–39.
Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med. 1991;325:373–81.
Carr MC, Brunzell JD, Deeb SS. Ethnic differences in hepatic lipase and HDL in Japanese, black, and white Americans: role of central obesity and LIPC polymorphisms. J Lipid Res. 2004;45(3):466–73.
Zambon A, Deeb SS, Hokanson JE, Brown BG, Brunzell JD. Common variants in the promoter of the hepatic lipase gene are associated with lower levels of hepatic lipase activity, buoyant LDL, and higher HDL2 cholesterol. Arterioscler Thromb Vasc Biol. 1998;18(11):1723–9.
Okumura K, Matsui H, Kamiya H, Saburi Y, Hayashi K, Hayakawa T. Differential effect of two common polymorphisms in the cholesteryl ester transfer protein gene on low density lipoprotein particle size. Atherosclerosis. 2002;161(2):425–31.
Collet X, Tall AR, Serajuddin H, Guendouzi K, Royer L, Oliveira H, et al. Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I. J Lipid Res. 1999;40:1185–93.
Santamarina-Fojo S, Haudenschild C, Amar M. The role of hepatic lipase in lipoprotein metabolism and atherosclerosis. Curr Opin Lipidol. 1998;9:211–9.
Boekholdt SM, Kuivenhoven JA, Hovingh GK, Jukema JW, Kastelein JJ, van Tol A. CETP gene variation: relation to lipid parameters and cardiovascular risk. Curr Opin Lipidol. 2004;15(4):393–8.
Borggreve SE, Hillege HL, Wolffenbuttel BH, de Jong PE, Bakker SJ, van der Steege G, et al. The effect of cholesteryl ester transfer protein −629C-A promoter polymorphism on high density lipoprotein cholesterol is dependent on serum triglycerides. J Clin Endocrinol Metab. 2005;90(7):4198–202.
Sakai N, Yamashita S, Hirano K, Menju M, Arai T, Kobayashi K, et al. Frequency of exon 15 missense mutation (442 D:G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects. J Lipid Res. 1995;114(2):139–45.
Su ZG, Zhang SZ, Hou YP, Zhang L, Huang DJ, Liao LC, et al. Relationship between a novel polymorphism of hepatic lipase gene and coronary artery disease. Acta Biochim Biophys Sin. 2002;34(6):780–5.
Hirano T, Ito Y, Saegusa H, Yoshino G. A novel and simple method for quantification of small, dense LDL. J Lipid Res. 2003;44(11):2193–201.
Couture P, Otvos JD, Cupples LA, Lahoz C, Wilson PW, Schaefer EJ, Ordovas JM. Association of the C-514T polymorphism in the hepatic lipase gene with variations in lipoprotein subclass profiles. The Framingham Offspring Study. Arterioscler Thromb Vasc Biol. 2000;20(3):815–22.
Kondkar AA, Nair KG, Ashavaid TF. Genetic analysis of Indian subjects with clinical features of possible type IIa hypercholesterolemia. J Clin Lab Anal. 2007;21(6):375–81.
Eghlim FF, Ashavaid TF, Nair KG. Genetic determinants of hyperhomocysteinemia in atherosclerosis. Indian J Clin Biochem. 2006;21(2):4–11.
Ashavaid TF, Todur SP, Nair KG. Apolipoprotein E4 polymorphism as risk factor for coronary heart disease among Indian subjects. Indian J Clin Biochem. 2002;17(1):83–93.
Padmaja N, Ravindra Kumar M, Soya SS, Adithan C. Common variants of cholesteryl ester transfer protein gene and their association with lipid parameters in healthy volunteers of Tamilian population. Clin Chim Acta. 2007;375:140–6. doi:10.1016/j.cca.2006.06.031.
Padmaja N, Kumar RM, Balachander J, Adithan C. Cholesteryl ester transfer protein TaqIB, −629C>A and I405V polymorphisms and risk of coronary heart disease in an Indian population. Clin Chim Acta. 2009;402:139–45. doi:10.1016/j.cca.2008.12.041.
Ghatreh SK, Noori M, Rohbani N, Hashemzadeh C, Farrokhi E, Darabi A. I405V and −629C/A polymorphisms of the cholesteryl ester transfer protein gene in patients with coronary artery disease. Iran Biomed J. 2009;13:103–8.
Park KW, Choi JH, Chae IH, Cho HJ, Oh S, Kim HS, et al. Hepatic lipase C514T polymorphism and its relationship with plasma HDL-C levels and coronary artery disease in Koreans. J Biochem Mol Biol. 2003;36:237–42.
Tai ES, Corella D, Deurenberg YM, Cutter J, Chew SK, Tan CE, et al. Dietary fat interacts with the −514C>T polymorphism in the hepatic lipase gene promoter on plasma lipid profiles in a multiethnic population: the 1998 Singapore National Health Survey. J Nutr. 2003;133(11):3399–408.
Vega GL, Clark LT, Tang A, Marcovina S, Grundy SM, Cohen JC. Hepatic lipase activity is lower in African American men than in white American men: effects of 5′ flanking polymorphism in the hepatic lipase gene (LIPC). J Lipid Res. 1998;39(1):228–32.
Thompson JF, Durham LK, Lira ME, Shear C, Milos PM. CETP polymorphisms associated with HDL cholesterol may differ from those associated with cardiovascular disease. Atherosclerosis. 181(1):45–53.
Wu JH, Lee YT, Hsu HC, Hsieh LL. Influence of CETP gene variation on plasma lipid levels and coronary heart disease: a survey in Taiwan. Atherosclerosis. 2001;159(2):451–8.
Freeman DJ, Samani NJ, Wilson V, McMahon AD, Braund PS, Cheng S, et al. A polymorphism of the cholesteryl ester transfer protein gene predicts cardiovascular events in non-smokers in the West of Scotland Coronary Prevention Study. Eur Heart J. 2003;24(20):1833–42.
Ashavaid TF, Todur SP, Dherai AJ. Health status of Indian population—current scenario. J Assoc Physicians India. 2004;52:363–9.
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(9):4532–7.
Soyal SM, Sandhofer A, Hahne P, Oberkofler H, Felder T, Iglseder B, et al. Cholesteryl ester transfer protein and hepatic lipase gene polymorphisms: effects on hepatic mRNA levels, plasma lipids and carotid atherosclerosis. Atherosclerosis. 2011;216(2):374–80.
Mahaney MC, Blangero J, Rainwater DL, Comuzzie AG, VandeBerg JL, Stern MP, et al. A major locus influencing plasma high-density lipoprotein cholesterol levels in the San Antonio family heart study. Segregation and linkage analyses. Arterioscler Thromb Vasc Biol. 1995;15(10):1730–9.
Carr MC, Ayyobi AF, Murdoch SJ, Deeb SS, Brunzell JD. Contribution of hepatic lipase, lipoprotein lipase, and cholesteryl ester transfer protein to LDL and HDL heterogeneity in healthy women. Arterioscler Thromb Vasc Biol. 2002;22(4):667–73.
Zambon A, Deeb SS, Brown G, Hokanson JE, Brunzell JD. Common hepatic lipase gene promoter variant determines clinical response to intensive lipid lowering treatment. Circulation. 2001;103:792–8.
Talmud PJ, Edwards KL, Turner CM, Newman B, Palmen JM, Humphries SE, et al. Linkage of the cholesteryl ester transfer protein (CETP) gene to LDL particle size: use of a novel tetranucleotide repeat within the CETP promoter. Circulation. 2000;101(21):2461–6.
Bruce C, Sharp DS, Tall AR. Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia. J Lipid Res. 1998;39(5):1071–8.
Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA. 2003;290(15):2030–40.
Thompson A, Angelantonio E, Sarwar N, Ergou S, Saleheen D, Dullaart RP, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA. 2008;299(23):2777–88.
Blankenberg S, Rupprecht HJ, Bickel C, Jiang XC, Poirier O, Lackner KJ, et al. Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease. J Am Coll Cardiol. 2003;41(11):1983–9.
Dherai AJ, Kondkar AA, Ashavaid TF. Determination of low density lipoprotein subfractions in normolipidemic individuals. Indian J Cardiol. 2003;6:41–5.
Acknowledgments
This work was funded by National Health Education Society (NHES) of P. D. Hinduja National Hospital and Medical Research Centre Mumbai, India.
Conflict of interest
The authors have no conflict of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Todur, S.P., Ashavaid, T.F. Association of CETP and LIPC Gene Polymorphisms with HDL and LDL Sub-fraction Levels in a Group of Indian Subjects: A Cross-Sectional Study. Ind J Clin Biochem 28, 116–123 (2013). https://doi.org/10.1007/s12291-012-0259-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12291-012-0259-y