The I405V and Taq1B polymorphisms of the CETP gene differentially affect sub-clinical carotid atherosclerosis

Lipids in Health and Disease

Eliana Cotta de Faria⁶  Eder Carlos Rocha Quintão³  Edna Regina Nakandakare³  Vanessa Helena de Souza Zago⁷  Ruy Tsutomu Nakamura⁵  Magnus Gidlund²  Andrei Carvalho Sposito¹  Luiz Sérgio Fernandes de Carvalho¹  José Ernesto dos Santos⁸  Helena Coutinho Franco de Oliveira⁴  Denise Kaplan⁷  Natália Baratella Panzoldo⁷  Eliane Soler Parra⁷ 

[1] Cardiology Division, Faculty of Medical Sciences, State University of Campinas, Rua Tessália Vieria de Camargo, 126, Campinas, SP, 13083-887, Brazil;Imunology Department, University of São Paulo, Av Prof. Lineu Prestes, 2415, São Paulo, SP, 05508-900, Brazil;Lipids Laboratory (LIM 10), Faculty of Medical Sciences of the University of São Paulo, Av Dr Arnaldo, 455, São Paulo, SP, 01246-903, Brazil;Lipids Laboratory, Biology Institute, State University of Campinas, Rua Monteiro Lobato, 255, Campinas, SP, 13083-862, Brazil;Department of Radiology, Faculty of Medical Sciences, State University of Campinas, Rua Tessália Vieira de Camargo, 126, Campinas, SP, 13083-887, Brazil;Departamento de Patologia Clínica, FCM-UNICAMP, P.O. Box 6111, Rua Tessália Vieira de Camargo, 126, Campinas, Barão Geraldo, SP 13084-971, Brazil;Lipids Laboratory, Faculty of Medical Sciences, State University of Campinas, Rua 5 de Junho, 350, Campinas, SP 13083-877, Brazil;Faculty of Medicine, University of São Paulo, Av Bandeirantes, 3900, Ribeirão Preto, SP, 14039-900, Brazil

关键词: Genetic polymorphism;    Cholesteryl ester transfer protein;    Carotid intima-media thickness;    Carotid atherosclerosis;   

Others  :  1160185
DOI  :  10.1186/1476-511X-11-130

 received in 2012-07-26, accepted in 2012-09-29,  发布年份 2012

【 摘 要 】

Background

Cholesteryl ester transfer protein (CETP) plays a major role in lipid metabolism, but studies on the association of CETP polymorphisms with risks of cardiovascular disease are inconsistent. This study investigated whether the CETP gene I405V and Taq1B polymorphisms modified subclinical atherosclerosis in an asymptomatic Brazilian population sample.

Methods

The polymorphisms were analyzed using polymerase chain reaction in 207 adult volunteers. Serum lipid profiles, oxLDL Ab titers, C-reactive protein and tumor necrosis factor-α concentrations and CETP and phospholipid transfer protein (PLTP) activities were determined, and common carotid artery intima-media thickness (cIMT) was measured using ultrasonography.

Results

No differences in cIMT were observed between the presence or absence of the minor B2 and V alleles in either polymorphism. However, inverse correlations between mean cIMT and CETP activity in the presence of these polymorphisms were observed, and positive correlations of these polymorphisms with PLTP activity and oxLDL Ab titers were identified. Moreover, logistic multivariate analysis revealed that the presence of the B2 allele was associated with a 5.1-fold (CI 95%, OR: 1.26 – 21.06) increased risk for cIMT, which was equal and above the 66^th percentile and positively interacted with age. However, no associations with the V allele or CETP and PLTP activities were observed.

Conclusions

None of the studied parameters, including CETP activity, explained the different relationships between these polymorphisms and cIMT, suggesting that other non-determined factors were affected by the genotypes and related to carotid atherosclerotic disease.

【 授权许可】

   
2012 Parra et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Glass CK, Witztum JL: Atherosclerosis the road ahead. Cell 2001, 104:503-516.
• [2]Parra ES, Urban A, Panzoldo NB, Nakamura RT, Oliveira R, De Faria EC: A reduction of CETP activity, not an increase, is associated with modestly impaired postprandial lipemia and increased HDL-cholesterol in adult asymptomatic women. Lipids Health Dis 2011, 10:87. BioMed Central Full Text
• [3]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
• [4]Boekholdt SM, Thompson JF: Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J Lipid Res 2003, 44:1080-1093.
• [5]Oliveira HC, De Faria EC: Cholesteryl ester transfer protein: the controversial relation to atherosclerosis and emerging new biological roles. IUBMB Life 2011, 63:248-257.
• [6]Savolainen MJ, Hannuksela M, Seppanen S, Kervinen K, Kesaniemi YA: Increased high-density lipoprotein cholesterol concentration in alcoholics is related to low cholesteryl ester transfer protein activity. Eur J Clin Invest 1990, 20:593-599.
• [7]Eyre J, Hammett F, Miller NE: A micro-method for the rapid ultracentrifugal separation of human plasma high density lipoprotein subfractions, HDL2 and HDL3. Clin Chim Acta 1981, 114:225-231.
• [8]Lagrost L: Determination of the mass concentration and the activity of the plasma cholesteryl ester transfer protein (CETP). Methods Mol Biol 1998, 110:231-241.
• [9]Damen J, Regts J, Scherphof G: Transfer of [14C]phosphatidylcholine between liposomes and human plasma high density lipoprotein. Partial purification of a transfer-stimulating plasma factor using a rapid transfer assay. Biochim Biophys Acta 1982, 712:444-452.
• [10]Gidlund M, Damasceno NR, Lindoso JA, Abdalla DS, Goto H: Monoclonal antibodies against low density lipoprotein with various degrees of oxidative modifications. Braz J Med Biol Res 1996, 29:1625-1628.
• [11]Salazar LA, Melo CE, Cavalli SA, Hinuy HM, Hirata MH, Hirata RDC: Micrométodo para extraçäo de DNA genômico útil no diagnóstico molecular da Hipercolesterolemia Familial. Rev bras anal clin 2001, 33:111-116.
• [12]Fumeron F, Betoulle D, Luc G, Behague I, Ricard S, Poirier O, Jemaa R, Evans A, Arveiler D, Marques-Vidal P, et al.: 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, 96:1664-1671.
• [13]Gudnason V, Kakko S, Nicaud V, Savolainen MJ, Kesaniemi YA, Tahvanainen E, Humphries S: Cholesteryl ester transfer protein gene effect on CETP activity and plasma high-density lipoprotein in European populations. The EARS Group. Eur J Clin Invest 1999, 29:116-128.
• [14]Simons PC, Algra A, Bots ML, Grobbee DE, Van der Graaf Y: Common carotid intima-media thickness and arterial stiffness: indicators of cardiovascular risk in high-risk patients. The SMART Study (Second Manifestations of ARTerial disease). Circulation 1999, 100:951-957.
• [15]Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005, 21:263-265.
• [16]Elosua R, Cupples LA, Fox CS, Polak JF, D'Agostino RA Sr, Wolf PA, O'Donnell CJ, Ordovas JM: Association between well-characterized lipoprotein-related genetic variants and carotid intimal medial thickness and stenosis: The Framingham Heart Study. Atherosclerosis 2006, 189:222-228.
• [17]Soyal SM, Sandhofer A, Hahne P, Oberkofler H, Felder T, Iglseder B, Miller K, Krempler F, Patsch JR, Paulweber B, Patsch W: Cholesteryl ester transfer protein and hepatic lipase gene polymorphisms: Effects on hepatic mRNA levels, plasma lipids and carotid atherosclerosis. Atherosclerosis 2011, 216:374-380.
• [18]Tsai MY, Johnson C, Kao WH, Sharrett AR, Arends VL, Kronmal R, Jenny NS, Jacobs DR Jr, Arnett D, O' Leary D, Post W: Cholesteryl ester transfer protein genetic polymorphisms, HDL cholesterol, and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2008, 200:359-367.
• [19]Cazita PM, Barbeiro DF, Moretti AI, Quintao EC, Soriano FG: Human cholesteryl ester transfer protein expression enhances the mouse survival rate in an experimental systemic inflammation model: a novel role for CETP. Shock 2008, 30:590-595.
• [20]Grion CM, Cardoso LT, Perazolo TF, Garcia AS, Barbosa DS, Morimoto HK, Matsuo T, Carrilho AJ: Lipoproteins and CETP levels as risk factors for severe sepsis in hospitalized patients. Eur J Clin Invest 2010, 40:330-338.
• [21]Jarvik GP, Rajagopalan R, Rosenthal EA, Wolfbauer G, McKinstry L, Vaze A, Brunzell J, Motulsky AG, Nickerson DA, Heagerty PJ, et al.: Genetic and nongenetic sources of variation in phospholipid transfer protein activity. J Lipid Res 2010, 51:983-990.
• [22]Chen HW, Kuo CL, Huang CS, Kuo SJ, Liu CS: Oxidized low-density lipoproteins, autoantibodies against oxidized low-density lipoproteins and carotid intima media thickness in a clinically healthy population. Cardiology 2008, 110:252-259.
• [23]Asztalos BF, Collins D, Cupples LA, Demissie S, Horvath KV, Bloomfield HE, Robins SJ, Schaefer EJ: Value of high-density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol 2005, 25:2185-2191.
• [24]Kim BS, Jung HS, Bang OY, Chung CS, Lee KH, Kim GM: Elevated serum lipoprotein(a) as a potential predictor for combined intracranial and extracranial artery stenosis in patients with ischemic stroke. Atherosclerosis 2010, 212:682-688.
• [25]Relvas WG, Izar MC, Helfenstein T, Fonseca MI, Colovati M, Oliveira A, Ihara SS, Han SW, Las Casas AA Jr, Fonseca FA: Relationship between gene polymorphisms and prevalence of myocardial infarction among diabetic and non-diabetic subjects. Atherosclerosis 2005, 178:101-105.
• [26]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, 12:111-123.