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Synergistic effect between apolipoprotein E and apolipoprotein A1 gene polymorphisms in the risk for coronary artery disease

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Abstract

Alterations in lipid metabolism and genetic predisposition are major risk factors for coronary artery disease (CAD). Variations in genes involved in lipid metabolism may act synergistically to confer risk or protection against CAD. The objective of the present study was to determine such interactions in variants of apolipoprotein E and apolipoprotein A1 genes. One hundred and forty subjects with clinically confirmed CAD and 100 unrelated normal subjects participated in the study. Multiple regression analysis was used to relate lipid and apolipoprotein profiles with genotypes. Odd ratios were calculated for various combinations of ApoE and ApoA1 genotypes. Prevalence of ApoE ‘E4’ and ApoA1 ‘A’ and ‘T’ alleles was significantly higher in patients than controls. Serum apolipoprotein E and apolipoprotein A1 levels were significantly lower in CAD patients than controls. When lipid parameters were related to genotypes, the polymorphisms associated to various markers were in agreement with previous reports. ApoE 2/4 genotype in combination with either ApoA1 heterozygous GA or CT genotype conferred higher risk of CAD. E3 allele in homozygous or heterozygous state in combination with ApoA1+83 CC genotype conferred highest protection (P < 0.05). Thus, it appears that ApoE and ApoA1 gene variants may act synergistically to associate with risk and protection against CAD.

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References

  1. Davignon J, Gregg RE, Sing CF (1988) Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 8:1–21

    PubMed  CAS  Google Scholar 

  2. Ilveskoski E, Perola M, Lehtimaki T, Laippala P, Savolainen V, Pajarinen J, Penttila A, Lalu KH, Mannikko A, Liesto KK, Koivula T, Karhunen PJ (1999) Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men: an autopsy study. Circulation 100:608–613

    PubMed  CAS  Google Scholar 

  3. Van Bockxmeer FM, Mamotte CD (1992) Apolipoprotein epsilon 4 homozygosity in young men with coronary heart disease. Lancet 340:879–880

    Article  PubMed  Google Scholar 

  4. Wilson PW, Schaefer EJ, Larson MG, Ordovas JM (1996) Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler Thromb Vasc Biol 16:1250–1255

    PubMed  CAS  Google Scholar 

  5. Lenzen HJ, Assmann G, Buchwalsky R, Schulte H (1986) Association of apolipoprotein E polymorphism, low-density lipoprotein cholesterol, and coronary artery disease. Clin Chem 32:778–781

    PubMed  CAS  Google Scholar 

  6. Utermann G, Hardewig A, Zimmer F (1984) Apolipoprotein E phenotypes in patients with myocardial infarction. Hum Genet 65:237–241

    Article  PubMed  CAS  Google Scholar 

  7. Ordovas JM, Civeira F, Genest J Jr, Craig S, Robbins AH, Meade T, Pocovi M, Frossard PM, Masharani U, Wilson PW et al (1991) Restriction fragment length polymorphisms of the apolipoprotein A-I, C-III, A-IV gene locus. Relationships with lipids, apolipoproteins, and premature coronary artery disease. Atherosclerosis 87:75–86

    Article  PubMed  CAS  Google Scholar 

  8. Wile DB, Barbir M, Gallagher J, Myant NB, Ritchie CD, Thompson GR, Humphries SE (1989) Apolipoprotein A-I gene polymorphisms: frequency in patients with coronary artery disease and healthy controls and association with serum apo A-I and HDL-cholesterol concentration. Atherosclerosis 78:9–18

    Article  PubMed  CAS  Google Scholar 

  9. Jeenah M, Kessling A, Miller N, Humphries S (1990) G to A substitution in the promoter region of the apolipoprotein AI gene is associated with elevated serum apolipoprotein AI and high density lipoprotein cholesterol concentrations. Mol Biol Med 7:233–241

    PubMed  CAS  Google Scholar 

  10. Meng QH, Pajukanta P, Valsta L, Aro A, Pietinen P, Tikkanen MJ (1997) Influence of apolipoprotein A-1 promoter polymorphism on lipid levels and responses to dietary change in Finnish adults. J Intern Med 241:373–378

    Article  PubMed  CAS  Google Scholar 

  11. Pagani F, Sidoli A, Giudici GA, Barenghi L, Vergani C, Baralle FE (1990) Human apolipoprotein A-I gene promoter polymorphism: association with hyperalphalipoproteinemia. J Lipid Res 31:1371–1377

    PubMed  CAS  Google Scholar 

  12. Paul-Hayase H, Rosseneu M, Robinson D, Van Bervliet JP, Deslypere JP, Humphries SE (1992) Polymorphisms in the apolipoprotein (apo) AI-CIII-AIV gene cluster: detection of genetic variation determining plasma apo AI, apo CIII and apo AIV concentrations. Hum Genet 88:439–446

    Article  PubMed  CAS  Google Scholar 

  13. Saha N, Tay JS, Low PS, Humphries SE (1994) Guanidine to adenine (G/A) substitution in the promoter region of the apolipoprotein AI gene is associated with elevated serum apolipoprotein AI levels in Chinese non-smokers. Genet Epidemiol 11:255–264

    Article  PubMed  CAS  Google Scholar 

  14. Xu CF, Angelico F, Del Ben M, Humphries S (1993) Role of genetic variation at the apo AI-CIII-AIV gene cluster in determining plasma apo AI levels in boys and girls. Genet Epidemiol 10:113–122

    Article  PubMed  CAS  Google Scholar 

  15. Barre DE, Guerra R, Verstraete R, Wang Z, Grundy SM, Cohen JC (1994) Genetic analysis of a polymorphism in the human apolipoprotein A-I gene promoter: effect on plasma HDL-cholesterol levels. J Lipid Res 35:1292–1296

    PubMed  CAS  Google Scholar 

  16. Civeira F, Pocovi M, Cenarro A, Garces C, Ordovas JM (1993) Adenine for guanine substitution −78 base pairs 5′ to the apolipoprotein (APO) A-I gene: relation with high density lipoprotein cholesterol and APO A-I concentrations. Clin Genet 44:307–312

    PubMed  CAS  Google Scholar 

  17. Wang XL, Liu SX, McCredie RM, Wilcken DE (1996) Polymorphisms at the 5′-end of the apolipoprotein AI gene and severity of coronary artery disease. J Clin Invest 98:372–377

    Article  PubMed  CAS  Google Scholar 

  18. Matsunga A, Sasaki J, Mori T (1995) Apolipoprotein A1 gene promoter polymorphism in patients with coronary heart disease and healthy controls. Nutr Metab Cardiovasc Dis 5:269

    Google Scholar 

  19. Chhabra S, Narang R, Krishnan LR, Vasisht S, Agarwal DP, Srivvastava LM, Manchana SC, Das N (2003) Apolipoprotein A1-75 G/A and Apolipoprotein c3 Sst1 Polymorphisms in the risk assessment of coronary artery disease. Trends Clin Biochem Lab Med 186–193

  20. Salah D, Bohnet K, Gueguen R, Siest G, Visvikis S (1997) Combined effects of lipoprotein lipase and apolipoprotein E polymorphisms on lipid and lipoprotein levels in the Stanislas cohort. J Lipid Res 38:904–912

    PubMed  CAS  Google Scholar 

  21. Zak I, Balcerzyk A, Sarecka B, Niemiec P, Ciemniewski Z, Dylag S (2005) Contemporaneous carrier-state of two or three “proatherosclerotic” variants of APOE, ICAM1, PPARA and PAI-1 genes differentiate CAD patients from healthy individuals. Clin Chim Acta 362:110–118

    Article  PubMed  CAS  Google Scholar 

  22. Wenham PR, Price WH, Blandell G (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet 337:1158–1159

    Article  PubMed  CAS  Google Scholar 

  23. Goel PK, Bharti BB, Pandey CM, Singh U, Tewari S, Kapoor A, Garg N, Sinha N (2003) A tertiary care hospital-based study of conventional risk factors including lipid profile in proven coronary artery disease. Indian Heart J 55:234–240

    PubMed  Google Scholar 

  24. Francis MC, Frohlich JJ (2001) Coronary artery disease in patients at low risk–apolipoprotein AI as an independent risk factor. Atherosclerosis 155:165–170

    Article  PubMed  CAS  Google Scholar 

  25. Ashavaid TF, Todur SP (2001) Study of lipoprotein (a) levels and apolipoprotein E polymorphism in subjects at risk for CHD. AACC Mol Pathol Div 13:2

    Google Scholar 

  26. Luthra K, Bharghav B, Chabbra S, Das N, Misra A, Agarwal DP, Pandey RM, Srivastava LM (2002) Apolipoprotein E polymorphism in Northern Indian patients with coronary heart disease: phenotype distribution and relation to serum lipids and lipoproteins. Mol Cell Biochem 232:97–102

    Article  PubMed  CAS  Google Scholar 

  27. Balgir PP, Kaur M (2003) Restriction isotyping of apolipoprotein E among populations of Punjab, northwestern India. Hum Biol 75:771–776

    Article  PubMed  Google Scholar 

  28. Thelma BK, Juyal RC, Dodge HH, Pandav R, Chandra V, Ganguli M (2001) APOE polymorphism in a rural older population-based sample in India. Hum Biol 73:135–144

    Article  PubMed  CAS  Google Scholar 

  29. Kamboh MI, Aston CE, Nestlerode CM, McAllister AE, Hamman RF (1996) Haplotype analysis of two APOA1/MspI polymorphisms in relation to plasma levels of apo A-I and HDL-cholesterol. Atherosclerosis 127:255–262

    Article  PubMed  CAS  Google Scholar 

  30. Minnich A, DeLangavant G, Lavigne J, Roederer G, Lussier-Cacan S, Davignon J (1995) G–>A substitution at position −75 of the apolipoprotein A-I gene promoter. Evidence against a direct effect on HDL cholesterol levels. Arterioscler Thromb Vasc Biol 15:1740–1745

    PubMed  CAS  Google Scholar 

  31. Sigurdsson G Jr, Gudnason V, Sigurdsson G, Humphries SE (1992) Interaction between a polymorphism of the apo A-I promoter region and smoking determines plasma levels of HDL and apo A-I. Arterioscler Thromb 12:1017–1022

    PubMed  CAS  Google Scholar 

  32. Talmud PJ, Ye S, Humphries SE (1994) Polymorphism in the promoter region of the apolipoprotein AI gene associated with differences in apolipoprotein AI levels: the European Atherosclerosis Research Study. Genet Epidemiol 11:265–280

    Article  PubMed  CAS  Google Scholar 

  33. Eichner JE, Kuller LH, Ferrell RE, Meilahn EN, Kamboh MI (1990) Phenotypic effects of apolipoprotein structural variation on lipid profiles. III. Contribution of apolipoprotein E phenotype to prediction of total cholesterol, apolipoprotein B, and low density lipoprotein cholesterol in the healthy women study. Arteriosclerosis 10:379–385

    PubMed  CAS  Google Scholar 

  34. Eto M, Watanabe K, Makino I (1989) Increased frequencies of apolipoprotein epsilon 2 and epsilon 4 alleles in patients with ischemic heart disease. Clin Genet 36:183–188

    PubMed  CAS  Google Scholar 

  35. Luc G, Bard JM, Arveiler D, Evans A, Cambou JP, Bingham A, Amouyel P, Schaffer P, Ruidavets JB, Cambien F et al (1994) Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction. The ECTIM Study. Arterioscler Thromb 14:1412–1419

    PubMed  CAS  Google Scholar 

  36. Stengard JH, Zerba KE, Pekkanen J, Ehnholm C, Nissinen A, Sing CF (1995) Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation 91:265–269

    PubMed  CAS  Google Scholar 

  37. Chhabra S, Narang R, Krishnan LR, Vasisht S, Agarwal DP, Srivastava LM, Manchanda SC, Das N (2002) Apolipoprotein C3 SstI polymorphism and triglyceride levels in Asian Indians. BMC Genet 3:9

    Article  PubMed  CAS  Google Scholar 

  38. Das S (2004) Presidential oration 2003 lipids, diabetes and coronary artery disease in Indians. Int J Diab Dev Countries 24:87

    Google Scholar 

  39. Batalla A, Alvarez R, Reguero JR, Hevia S, Iglesias-Cubero G, Alvarez V, Cortina A, Gonzalez P, Celada MM, Medina A, Coto E (2000) Synergistic effect between apolipoprotein E and angiotensinogen gene polymorphisms in the risk for early myocardial infarction. Clin Chem 46:1910–1915

    PubMed  CAS  Google Scholar 

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Financial support to this work was provided by Indian Council for Medical Research (ICMR).

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Correspondence to Madhu Khullar.

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Rai, T.S., Khullar, M., Sehrawat, B.S. et al. Synergistic effect between apolipoprotein E and apolipoprotein A1 gene polymorphisms in the risk for coronary artery disease. Mol Cell Biochem 313, 139–146 (2008). https://doi.org/10.1007/s11010-008-9751-3

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  • DOI: https://doi.org/10.1007/s11010-008-9751-3

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