Association of cholesteryl ester transfer protein (CETP) gene polymorphism, high density lipoprotein cholesterol and risk of coronary artery disease: a meta-analysis using a Mendelian randomization approach

BMC Medical Genetics

Wei Jin¹  Qiujing Chen¹  Lin Lu¹  Yan Liu¹  Xiaochun Qiu²  Yuqing Lou³  Zhijun Wu¹ 

[1] Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China;Library of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China;Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People’s Republic of China

关键词: Mendelian randomization;    Polymorphism;    High density lipoprotein cholesterol;    Coronary artery disease;   

Others  :  1090330
DOI  :  10.1186/s12881-014-0118-1

 received in 2014-04-21, accepted in 2014-10-10,  发布年份 2014

【 摘 要 】

Background

Recent randomized controlled trials have challenged the concept that increased high density lipoprotein cholesterol (HDL-C) levels are associated with coronary artery disease (CAD) risk reduction. The causal role of HDL-C in the development of atherosclerosis remains unclear. To increase precision and to minimize residual confounding, we exploited the cholesteryl ester transfer protein (CETP)-TaqIB polymorphism as an instrument based on Mendelian randomization.

Methods

The Mendelian randomization analysis was performed by two steps. First, we conducted a meta-analysis of 47 studies, including 23,928 cases and 27,068 controls, to quantify the relationship between the TaqIB polymorphism and the CAD risk. Next, the association between the TaqIB polymorphism and HDL-C was assessed among 5,929 Caucasians. We further employed Mendelian randomization to evaluate the causal effect of HDL-C on CAD based on the findings from the meta-analysis.

Results

The overall comparison of the B2 allele with the B1 allele yielded a significant risk reduction of CAD (P < 0.0001; OR = 0.88; 95% CI: 0.84–0.92) with substantial between-study heterogeneity (I² = 55.2%; P_{heterogeneity} <0.0001). The result was not materially changed after excluding the Hardy-Weinberg Equilibrium (HWE)-violation studies. Compared with B1B1 homozygotes, Caucasian carriers of the B2 allele had a 0.25 mmol/L increase in HDL-C level (95% CI: 0.20–0.31; P <0.0001; I² = 0; P_{heterogeneity} =0.87). However, a 1 standard deviation (SD) elevation in HDL-C levels due to the TaqIB polymorphism, was marginal associated with CAD risk (OR =0.79; 95% CI: 0.54–1.03; P =0.08).

Conclusions

Taken together, our results lend support to the concept that increased HDL-C cannot be translated into a reduction in CAD risk.

【 授权许可】

   
2014 Wu et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) JAMA 2001, 285(19):2486-2497.
• [2]Shah S, Casas JP, Gaunt TR, Cooper J, Drenos F, Zabaneh D, Swerdlow DI, Shah T, Sofat R, Palmen J, Kumari M, Kivimaki M, Ebrahim S, Smith GD, Lawlor DA, Talmud PJ, Whittaker J, Day IN, Hingorani AD, Humphries SE: Influence of common genetic variation on blood lipid levels, cardiovascular risk, and coronary events in two British prospective cohort studies. Eur Heart J 2013, 34(13):972-981.
• [3]High HDL may not protect the heart. Concentrate on lowering LDL for now, experts advise.Harv Heart Lett 2012, 23(1):6.
• [4]Is “good” cholesterol still good for you? New research questions the benefit of drugs to raise HDL, but lifestyle steps to boost good cholesterol are still recommended.Harv Mens Health Watch 2012, 17(2):3.
• [5]Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP: Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010, 362(17):1563-1574.
• [6]Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study Circulation 2000, 102(1):21-27.
• [7]Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR: High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977, 62(5):707-714.
• [8]Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B: Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007, 357(21):2109-2122.
• [9]Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS: Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012, 367(22):2089-2099.
• [10]Barter PJ, Brewer HB Jr, 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(2):160-167.
• [11]Schierer A, Been LF, Ralhan S, Wander GS, Aston CE, Sanghera DK: Genetic variation in cholesterol ester transfer protein, serum CETP activity, and coronary artery disease risk in Asian Indian diabetic cohort. Pharmacogenet Genomics 2012, 22(2):95-104.
• [12]Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, et al.: Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009, 41(1):56-65.
• [13]Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, et al.: Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009, 41(1):47-55.
• [14]Ordovas JM, Cupples LA, Corella D, Otvos JD, Osgood D, Martinez A, Lahoz C, Coltell O, Wilson PW, Schaefer EJ: Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk: the Framingham study. Arterioscler Thromb Vasc Biol 2000, 20(5):1323-1329.
• [15]Kondo I, Berg K, Drayna D, Lawn R: DNA polymorphism at the locus for human cholesteryl ester transfer protein (CETP) is associated with high density lipoprotein cholesterol and apolipoprotein levels. Clin Genet 1989, 35(1):49-56.
• [16]Dachet C, Poirier O, Cambien F, Chapman J, Rouis M: New functional promoter polymorphism, CETP/-629, in cholesteryl ester transfer protein (CETP) gene related to CETP mass and high density lipoprotein cholesterol levels: role of Sp1/Sp3 in transcriptional regulation. Arterioscler Thromb Vasc Biol 2000, 20(2):507-515.
• [17]Horne BD, Camp NJ, Anderson JL, Mower CP, Clarke JL, Kolek MJ, Carlquist JF: Multiple less common genetic variants explain the association of the cholesteryl ester transfer protein gene with coronary artery disease. J Am Coll Cardiol 2007, 49(20):2053-2060.
• [18]Boekholdt SM, Sacks FM, Jukema JW, Shepherd J, Freeman DJ, McMahon AD, Cambien F, Nicaud V, de Grooth GJ, Talmud PJ, Humphries SE, Miller GJ, Eiriksdottir G, Gudnason V, Kauma H, Kakko S, Savolainen MJ, Arca M, Montali A, Liu S, Lanz HJ, Zwinderman AH, Kuivenhoven JA, Kastelein JJ: Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects. Circulation 2005, 111(3):278-287.
• [19]Thompson A, Di Angelantonio E, Sarwar N, Erqou S, Saleheen D, Dullaart RP, Keavney B, Ye Z, Danesh J: Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA 2008, 299(23):2777-2788.
• [20]Liu S, Schmitz C, Stampfer MJ, Sacks F, Hennekens CH, Lindpaintner K, Ridker PM: A prospective study of TaqIB polymorphism in the gene coding for cholesteryl ester transfer protein and risk of myocardial infarction in middle-aged men. Atherosclerosis 2002, 161(2):469-474.
• [21]Whiting BM, Anderson JL, Muhlestein JB, Horne BD, Bair TL, Pearson RR, Carlquist JF: Candidate gene susceptibility variants predict intermediate end points but not angiographic coronary artery disease. Am Heart J 2005, 150(2):243-250.
• [22]McCaskie PA, Beilby JP, Chapman CM, Hung J, McQuillan BM, Thompson PL, Palmer LJ: Cholesteryl ester transfer protein gene haplotypes, plasma high-density lipoprotein levels and the risk of coronary heart disease. Hum Genet 2007, 121(3–4):401-411.
• [23]Borggreve SE, Hillege HL, Wolffenbuttel BH, de Jong PE, Zuurman MW, van der Steege G, van Tol A, Dullaart RP: An increased coronary risk is paradoxically associated with common cholesteryl ester transfer protein gene variations that relate to higher high-density lipoprotein cholesterol: a population-based study. J Clin Endocrinol Metab 2006, 91(9):3382-3388.
• [24]Smith GD, Ebrahim S: ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003, 32(1):1-22.
• [25]Castle WE: Mendel’s law of heredity. Science 1903, 18(456):396-406.
• [26]Niu W, Liu Y, Qi Y, Wu Z, Zhu D, Jin W: Association of interleukin-6 circulating levels with coronary artery disease: a meta-analysis implementing mendelian randomization approach. Int J Cardiol 2012, 157(2):243-252.
• [27]Wright RS, Anderson JL, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Jneid H, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP, Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Zidar JP: 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol 2011, 57(19):e215-e367.
• [28]Joensen AM, Jensen MK, Overvad K, Dethlefsen C, Schmidt E, Rasmussen L, Tjonneland A, Johnsen S: Predictive values of acute coronary syndrome discharge diagnoses differed in the Danish National Patient Registry. J Clin Epidemiol 2009, 62(2):188-194.
• [29]Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A: Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 1994, 90(1):583-612.
• [30]Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J: A method for meta-analysis of molecular association studies. Stat Med 2005, 24(9):1291-1306.
• [31]Cohn LD, Becker BJ: How meta-analysis increases statistical power. Psychol Methods 2003, 8(3):243-253.
• [32]Higgins JP, Thompson SG: Quantifying heterogeneity in a meta-analysis. Stat Med 2002, 21(11):1539-1558.
• [33]Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ 2003, 327(7414):557-560.
• [34]Lau J, Ioannidis JP, Schmid CH: Quantitative synthesis in systematic reviews. Ann Intern Med 1997, 127(9):820-826.
• [35]Egger M, Davey Smith G, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 315(7109):629-634.
• [36]Arca M, Montali A, Ombres D, Battiloro E, Campagna F, Ricci G, Verna R: Lack of association of the common TaqIB polymorphism in the cholesteryl ester transfer protein gene with angiographically assessed coronary atherosclerosis. Clin Genet 2001, 60(5):374-380.
• [37]van Acker BA, Botma GJ, Zwinderman AH, Kuivenhoven JA, Dallinga-Thie GM, Sijbrands EJ, Boer JM, Seidell JC, Jukema JW, Kastelein JJ, Jansen H, Verhoeven AJ: High HDL cholesterol does not protect against coronary artery disease when associated with combined cholesteryl ester transfer protein and hepatic lipase gene variants. Atherosclerosis 2008, 200(1):161-167.
• [38]Bhanushali AA, Das BR: Genetic variants at the APOE, lipoprotein lipase (LpL), cholesteryl ester transfer protein (CETP), and endothelial nitric oxide (eNOS) genes and coronary artery disease (CAD): CETP Taq1 B2B2 associates with lower risk of CAD in Asian Indians. J Community Genet 2010, 1(2):55-62.
• [39]Blankenberg S, Tiret L, Bickel C, Schlitt A, Jungmair W, Genth-Zotz S, Lubos E, Espinola-Klein C, Rupprecht HJ: [Genetic variation of the cholesterol ester transfer protein gene and the prevalence of coronary artery disease. The AtheroGene case control study]. Z Kardiol 2004, 93(Suppl 4):IV16-IV23.
• [40]Corella D, Carrasco P, Amiano P, Arriola L, Chirlaque MD, Huerta JM, Martinez C, Martinez-Camblor P, Molina E, Navarro C, Quirós JR, Rodríguez L, Sánchez MJ, Ortega-Azorín C, Ros E, Sala N, González CA, Moreno C: Common cholesteryl ester transfer protein gene variation related to high-density lipoprotein cholesterol is not associated with decreased coronary heart disease risk after a 10-year follow-up in a Mediterranean cohort: Modulation by alcohol consumption. Atherosclerosis 2010, 211(2):531-538.
• [41]Dedoussis GV, Panagiotakos DB, Louizou E, Mantoglou I, Chrysohoou C, Lamnisou K, Pitsavos C, Stefanadis C: Cholesteryl ester-transfer protein (CETP) polymorphism and the association of acute coronary syndromes by obesity status in Greek subjects: the CARDIO2000-GENE study. Hum Hered 2007, 63(3–4):155-161.
• [42]Durlach A, Clavel C, Girard-Globa A, Durlach V: Sex-dependent association of a genetic polymorphism of cholesteryl ester transfer protein with high-density lipoprotein cholesterol and macrovascular pathology in type II diabetic patients. J Clin Endocrinol Metab 1999, 84(10):3656-3659.
• [43]Eiriksdottir G, Bolla MK, Thorsson B, Sigurdsson G, Humphries SE, Gudnason V: The -629C > A polymorphism in the CETP gene does not explain the association of TaqIB polymorphism with risk and age of myocardial infarction in Icelandic men. Atherosclerosis 2001, 159(1):187-192.
• [44]Falchi A, Giovannoni L, Piras IS, Calo CM, Moral P, Vona G, Varesi L: Prevalence of genetic risk factors for coronary artery disease in Corsica island (France). Exp Mol Pathol 2005, 79(3):210-213.
• [45]Freeman DJ, Samani NJ, Wilson V, McMahon AD, Braund PS, Cheng S, Caslake MJ, Packard CJ, Gaffney D: 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):1833-1842.
• [46]Fumeron F, Betoulle D, Luc G, Behague I, Ricard S, Poirier O, Jemaa R, Evans A, Arveiler D, Marques-Vidal P: Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction. J Clin Invest 1995, 96(3):1664-1671.
• [47]Hsieh MC, Tien KJ, Chang SJ, Lo CS, Hsin SC, Hsiao JY, Hsu SC, Liang HT, Chen HC, Shin SJ, Lin SR: Cholesteryl ester transfer protein B1B1 genotype as a predictor of coronary artery disease in Taiwanese with type 2 diabetes mellitus. Metabolism 2007, 56(6):745-750.
• [48]Izar MC, Helfenstein T, Ihara SS, Relvas WG, Santos AO, Fischer SC, Pinto LE, Lopes IE, Pomaro DR, Fonseca MI, Bodanese LC, Moriguchi EH, Saraiva JF, Introcaso L, Souza AD, Scartezini M, Torres KP, Zagury L, Jardim PC, Costa EA, Tacito LH, Forti A, Magalhaes ME, Chacra AR, Bertolami MC, Loures-Vale AA, Barros MA, Xavier HT, Lyra R, Argamanijan D, et al.: Association of lipoprotein lipase D9N polymorphism with myocardial infarction in type 2 diabetes: the genetics, outcomes, and lipids in type 2 diabetes (GOLD) study. Atherosclerosis 2009, 204(1):165-170.
• [49]Jensen MK, Mukamal KJ, Overvad K, Rimm EB: Alcohol consumption, TaqIB polymorphism of cholesteryl ester transfer protein, high-density lipoprotein cholesterol, and risk of coronary heart disease in men and women. Eur Heart J 2008, 29(1):104-112.
• [50]Kaestner S, Patsouras N, Spathas DH, Flordellis CS, Manolis AS: Lack of association between the cholesteryl ester transfer protein gene–TaqIB polymorphism and coronary restenosis following percutaneous transluminal coronary angioplasty and stenting: a pilot study. Angiology 2010, 61(4):338-343.
• [51]Kawasaki I, Tahara H, Emoto M, Shoji T, Nishizawa Y: Relationship between TaqIB cholesteryl ester transfer protein gene polymorphism and macrovascular complications in Japanese patients with type 2 diabetes. Diabetes 2002, 51(3):871-874.
• [52]Keavney B, Palmer A, Parish S, Clark S, Youngman L, Danesh J, McKenzie C, Delepine M, Lathrop M, Peto R, Collins R: Lipid-related genes and myocardial infarction in 4685 cases and 3460 controls: discrepancies between genotype, blood lipid concentrations, and coronary disease risk. Int J Epidemiol 2004, 33(5):1002-1013.
• [53]Kolovou G, Vasiliadis I, Kolovou V, Karakosta A, Mavrogeni S, Papadopoulou E, Papamentzelopoulos S, Giannakopoulou V, Marvaki A, Degiannis D, Bilianou H: The role of common variants of the cholesteryl ester transfer protein gene in left main coronary artery disease. Lipids Health Dis 2011, 10:156. BioMed Central Full Text
• [54]Meiner V, Friedlander Y, Milo H, Sharon N, Ben-Avi L, Shpitzen S, Leitersdorf E, Siscovick DS, Schwartz SM: Cholesteryl ester transfer protein (CETP) genetic variation and early onset of non-fatal myocardial infarction. Ann Hum Genet 2008, 72(Pt 6):732-741.
• [55]Mohrschladt MF, van der Sman-de BF, Hofman MK, van der Krabben M, Westendorp RG, Smelt AH: TaqIB polymorphism in CETP gene: the influence on incidence of cardiovascular disease in statin-treated patients with familial hypercholesterolemia. Eur J Hum Genet 2005, 13(7):877-882.
• [56]Muendlein A, Saely CH, Marte T, Schmid F, Koch L, Rein P, Langer P, Aczel S, Drexel H: Synergistic effects of the apolipoprotein E epsilon3/epsilon2/epsilon4, the cholesteryl ester transfer protein TaqIB, and the apolipoprotein C3–482 C > T polymorphisms on their association with coronary artery disease. Atherosclerosis 2008, 199(1):179-186.
• [57]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(1–2):139-145.
• [58]Poduri A, Khullar M, Bahl A, Sharma YP, Talwar KK: A combination of proatherogenic single-nucleotide polymorphisms is associated with increased risk of coronary artery disease and myocardial infarction in Asian Indians. DNA Cell Biol 2009, 28(9):451-460.
• [59]Porchay-Balderelli I, Pean F, Bellili N, Jaziri R, Marre M, Fumeron F: The CETP TaqIB polymorphism is associated with the risk of sudden death in type 2 diabetic patients. Diabetes Care 2007, 30(11):2863-2867.
• [60]Rahimi Z, Nourozi-Rad R, Vaisi-Raygani A, Saidi MR, Ahmadi R, Yarani R, Hamzehee K, Parsian A: Association between cholesteryl ester transfer protein TaqIB variants and risk of coronary artery disease and diabetes mellitus in the population of western Iran. Genet Test Mol Biomarkers 2011, 15(11):813-819.
• [61]Rejeb J, Omezzine A, Rebhi L, Naffeti I, Kchok K, Belkahla R, Bel Hadjmbarek I, Ben Rejeb N, Nabli N, Boujelbene A, Ben Abdelaziz A, Boughzala E, Bouslama A: Association of the cholesteryl ester transfer protein Taq1 B2B2 genotype with higher high-density lipoprotein cholesterol concentrations and lower risk of coronary artery disease in a Tunisian population. Arch Cardiovasc Dis 2008, 101(10):629-636.
• [62]Tenkanen H, Koshinen P, Kontula K, Aalto-Setala K, Manttari M, Manninen V, Runeberg SL, Taskinen MR, Ehnholm C: Polymorphisms of the gene encoding cholesterol ester transfer protein and serum lipoprotein levels in subjects with and without coronary heart disease. Hum Genet 1991, 87(5):574-578.
• [63]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):451-458.
• [64]Yilmaz H, Isbir T, Agachan B, Karaali ZE: Effects of cholesterol ester transfer protein Taq1B gene polymorphism on serum lipoprotein levels in Turkish coronary artery disease patients. Cell Biochem Funct 2005, 23(1):23-28.
• [65]Zheng KQ, Zhang SZ, He Y, Zhang L, Zhang KL, Huang DJ, Sun Y: Association between cholesteryl ester transfer protein gene polymorphisms and variations in lipid levels in patients with coronary heart disease. Chin Med J 2004, 117(9):1288-1292.
• [66]Park KW, Choi JH, Kim HK, Oh S, Chae IH, Kim HS, Oh BH, Lee MM, Park YB, Choi YS: The association of cholesteryl ester transfer protein polymorphism with high-density lipoprotein cholesterol and coronary artery disease in Koreans. Clin Genet 2003, 63(1):31-38.
• [67]Blankenberg S, Rupprecht HJ, Bickel C, Jiang XC, Poirier O, Lackner KJ, Meyer J, Cambien F, Tiret L: 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):1983-1989.
• [68]Wu Z, Lou Y, Jin W, Liu Y, Lu L, Lu G: The C161T polymorphism in the peroxisome proliferator-activated receptor gamma gene (PPARgamma) is associated with risk of coronary artery disease: a meta-analysis. Mol Biol Rep 2013, 40(4):3101-3112.
• [69]Xing G, Xing C: Adjusting for covariates in logistic regression models. Genet Epidemiol 2010, 34(7):769-771. author reply 772
• [70]Minelli C, Thompson JR, Tobin MD, Abrams KR: An integrated approach to the meta-analysis of genetic association studies using Mendelian randomization. Am J Epidemiol 2004, 160(5):445-452.
• [71]Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report Circulation 2002, 106(25):3143-3421.
• [72]Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Beckmann JS, Bragg-Gresham JL, Chang HY, Demirkan A, Den Hertog HM, Do R, Donnelly LA, Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K, Fontanillas P, Fraser RM, Freitag DF, Gurdasani D, Heikkilä K, Hyppönen E, Isaacs A, Jackson AU, et al.: Discovery and refinement of loci associated with lipid levels. Nat Genet 2013, 45(11):1274-1283.
• [73]Frazier-Wood AC, Manichaikul A, Aslibekyan S, Borecki IB, Goff DC, Hopkins PN, Lai CQ, Ordovas JM, Post WS, Rich SS, Sale MM, Siscovick D, Straka RJ, Tiwari HK, Tsai MY, Rotter JI, Arnett DK: Genetic variants associated with VLDL, LDL and HDL particle size differ with race/ethnicity. Hum Genet 2013, 132(4):405-413.
• [74]Deo RC, Wilson JG, Xing C, Lawson K, Kao WH, Reich D, Tandon A, Akylbekova E, Patterson N, Mosley TH Jr, Boerwinkle E, Taylor HA Jr: Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans. PLoS ONE 2011, 6(1):e14581.
• [75]Colhoun HM, McKeigue PM, Davey Smith G: Problems of reporting genetic associations with complex outcomes. Lancet 2003, 361(9360):865-872.
• [76]Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G: Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008, 27(8):1133-1163.
• [77]Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, Hindy G, Holm H, Ding EL, Johnson T, Schunkert H, Samani NJ, Clarke R, Hopewell JC, Thompson JF, Li M, Thorleifsson G, Newton-Cheh C, Musunuru K, Pirruccello JP, Saleheen D, Chen L, Stewart A, Schillert A, Thorsteinsdottir U, Thorgeirsson G, Anand S, Engert JC, Morgan T, Spertus J, et al.: Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012, 380(9841):572-580.
• [78]Klerkx AH, Tanck MW, Kastelein JJ, Molhuizen HO, Jukema JW, Zwinderman AH, Kuivenhoven JA: 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(2):111-123.
• [79]Corbex M, Poirier O, Fumeron F, Betoulle D, Evans A, Ruidavets JB, Arveiler D, Luc G, Tiret L, Cambien F: Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction. Genet Epidemiol 2000, 19(1):64-80.
• [80]Van Eck M, Ye D, Hildebrand RB, Kar Kruijt J, de Haan W, Hoekstra M, Rensen PC, Ehnholm C, Jauhiainen M, Van Berkel TJ: Important role for bone marrow-derived cholesteryl ester transfer protein in lipoprotein cholesterol redistribution and atherosclerotic lesion development in LDL receptor knockout mice. Circ Res 2007, 100(5):678-685.
• [81]Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, Shinkai H: A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 2000, 406(6792):203-207.
• [82]Marotti KR, Castle CK, Boyle TP, Lin AH, Murray RW, Melchior GW: Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature 1993, 364(6432):73-75.
• [83]Plump AS, Masucci-Magoulas L, Bruce C, Bisgaier CL, Breslow JL, Tall AR: Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler Thromb Vasc Biol 1999, 19(4):1105-1110.
• [84]Herrera VL, Makrides SC, Xie HX, Adari H, Krauss RM, Ryan US, Ruiz-Opazo N: Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein. Nat Med 1999, 5(12):1383-1389.
• [85]Foger B, Chase M, Amar MJ, Vaisman BL, Shamburek RD, Paigen B, Fruchart-Najib J, Paiz JA, Koch CA, Hoyt RF, Brewer HB Jr, Santamarina-Fojo S: Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice. J Biol Chem 1999, 274(52):36912-36920.
• [86]Berti JA, de Faria EC, Oliveira HC: Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes. Braz J Med Biol Res 2005, 38(3):391-398.
• [87]Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W: Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011, 365(24):2255-2267.
• [88]Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, Mohler ER, Rothblat GH, Rader DJ: Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011, 364(2):127-135.
• [89]von Eckardstein A, Nofer JR, Assmann G: High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol 2001, 21(1):13-27.
• [90]Huang Y, DiDonato JA, Levison BS, Schmitt D, Li L, Wu Y, Buffa J, Kim T, Gerstenecker GS, Gu X, Kadiyala CS, Wang Z, Culley MK, Hazen JE, Didonato AJ, Fu X, Berisha SZ, Peng D, Nguyen TT, Liang S, Chuang CC, Cho L, Plow EF, Fox PL, Gogonea V, Tang WH, Parks JS, Fisher EA, Smith JD, Hazen SL: An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med 2014, 20(2):193-203.
• [91]Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, et al.: Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010, 466(7307):707-713.
• [92]Smith GD, Ebrahim S: Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 2004, 33(1):30-42.