Association study between DNA methylation and genetic variation of APOE gene with the risk of coronary artery disease

Document Type: Original article

Authors

1 Department of Pharmacology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

2 Department of Hematology and Blood Transfusion, School of Allied Medical Sciences, Lorestan University of Medical Sciences, Khorramabad, Iran

3 Department of Medical Laboratory Sciences, School of Paramedical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran

Abstract

Coronary artery disease (CAD) is a common health problem with a high rate of disability and death. Dyslipidemia and altered metabolism of Apo-lipoproteins are involved in the CAD pathogenesis. The current study investigated two common polymorphisms (rs429358 and rs7412) and promoter DNA methylation status of APOE in the Iranian CAD patients and control subjects. Two hundred angiographically documented CAD patients and 200 control subjects were included in the study. The APOE polymorphism analysis was done by PCR-RFLP technique and DNA methylation status was evaluated by methylation specific PCR. The assay of lipid levels was conducted using standard colorimetric protocols.Results indicated that the frequency of ε3/ε4 and ε2/ε3 genotypes was significantly more common in CAD group compared with control group. Relative to wild type genotype (ε3/ε3), CAD patients with ε3/ε4 and ε2/ε3 genotypes displayed significantly higher concentration of total-cholesterol and LDL-cholesterol. The frequency of DNA methylation of APOE was similar between the two studied groups. However, the methylation frequency of APOE gene was significantly higher in triple stenotic vessels relative to single stenotic vessels (P=0.032). In conclusion The present study indicated that the rs429358 and rs7412 polymorphisms are significantly risk factors for development and severity of CAD. Also, APOE methylation status may be involved in the severity but not in the development of CAD.

Keywords


1. Abi Khalil C. The emerging role of epigenetics in cardiovascular disease. Ther Adv Chronic Dis 2014;5:178-187.

2. Mahalle N, Garg MK, Naik SS, Kulkarni MV. Study of pattern of dyslipidemia and its correlation with cardiovascular risk factors in patients with proven coronary artery disease. Indian J Endocrinol Metab 2014;18:48-55.

3. Larifla L, Armand C, Bangou J, Blanchet-Deverly A, Numeric P, Fonteau C, Michel CT, Ferdinand S, Bourrhis V, Vélayoudom-Céphise FL. Association of APOE gene polymorphism with lipid profile and coronary artery disease in Afro-Caribbeans. PLoS One 2017;12:e0181620.

4. Granér M, Kahri J, Varpula M, Salonen RM, Nyyssönen K, Jauhiainen M, Nieminen MS, Syvänne M, Taskinen MR. Apolipoprotein E polymorphism is associated with both carotid and coronary atherosclerosis in patients with coronary artery disease. Nutr Metab Cardiovasc Dis 2008;18:271-277.

5. Atis O, Sahin S, Ceyhan K, Ozyurt H, Akbas A, Benli I. The Distribution of apolipoprotein E gene polymorphism and apolipoprotein E levels among coronary artery patients compared to controls. Eurasian J Med 2016;48:90-94.

6. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240:622-630.

7. Walden CC, Hegele RA. Apolipoprotein E in hyperlipidemia. Ann Intern Med 1994;120: 1026-1036.

8. Zhen J, Huang X, Halm-Lutterodt V, Dong S, Ma W, Xiao R, Yuan L. ApoE rs429358 and rs7412 Polymorphism and gender differences of serum lipid profile and cognition in aging Chinese population. Front Aging Neurosci 2017;9:248.

9. Evans D, Beil F. Genetic factors that modify the expression of type III hyperlipidemia in probands with apolipoprotein E ε2/2 genotype. Clin Lipidol 2009;4:137-140.

10. Yousuf FA, Iqbal MP. Apolipoprotein E (Apo E) gene polymorphism and coronary heart disease in Asian populations. Pak J Pharm Sci 2015;28:1439-1444.

11. Elmadbouh I, Elghobashy Y, Abd-Allah E, Reda AA, Fathe A, Tayel S, Abd-Elhakim T. Relationship of apolipoprotein E polymorphism with lipid profiles in atherosclerotic coronary artery disease. Egypt Heart J 2013;1;65:71-78.

12. Wu LH, Wu JT, Hopkins P. Apolipoprotein E: laboratory determinations and clinical significance. In: Rifai N, Warnick GH, Dominiczak MH (Editors), Handbook of lipoprotein testing. Washington: AACC Press; 1997. p598.

13. Davignon J CJ, Mabile L, Bernier L. Apolipoprotein E and atherosclerosis: Insight from animal and human studies. Clin Chim Acta 1999;286:115-143.

14. Eichner JE DS, Perveen G, Thompson DM, Stewart KE, Stroehla BC. Apolipoprotein E polymorphism and cardiovascular disease: A HuGE review. Am J Epidemiol 2002;155:487-495.

15. Xu M ZJ, Zhang Y, Ma X, Dai Q, Zhi H, Wang B, Wang L. Apolipoprotein E gene variants and risk of coronary heart disease: A meta-analysis. Biomed Res Int 2016;2016:3912175.

16. Mittelstraß K,  Waldenberger M. DNA methylation in human lipid metabolism and related diseases. Curr Opin Lipidol 2018;29:116-124.

17. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacol-ogy 2013;38:23-38.

18. Liu J, Zhao W, Ware EB, Turner ST, Mosley TH, Smith JA. DNA methylation in the APOE genomic region is associated with cognitive function in African Americans. BMC Med Genomics 2018;11:43.

19. Kordi-Tamandani DM, Najafi M, Mojahad A. Apoe and cpt1-a promoter methylation and expression profiles in patients with schizophrenia. Gene Cell Tissue 2014;1.

20. Karlsson IK, Ploner A, Wang Y, Gatz M, Pedersen NL, Hägg S. Apolipoprotein E DNA methylation and late-life disease. Int J Epidemiol 2018;47:899-907.

21. Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics 2002;18:1427-1431.

22. Corbo RM, Scacchi R. Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a 'thrifty' allele? Ann Hum Genet 1999;63:301-310.

23. Anuurad E, Rubin J, Lu G, Pearson TA, Holleran S, Ramakrishnan R, Berglund L. Protective effect of apolipoprotein E2 on coronary artery disease in African Americans is mediated through lipoprotein cholesterol. J Lipid Res 2006;47:2475-2481.

24. Li SS, Yang J, Li LS, Wang HC. Apolipoprotein E polymorphism and the characteristics of diseased vessels in male Chinese patients with angiographic coronary artery disease: a case-case study. Clin Cardiol 2010;33:E30-E34.

25. Zhao QR, Lei YY, Li J, Jiang N, Shi JP. Association between apolipoprotein E polymorphi-sms and premature coronary artery disease: a meta-analysis. Clin Chem Lab Med 2017;55: 284-298.

26. Afroze D, Yousuf A, Tramboo NA, Shah ZA, Ahmad A. ApoE gene polymorphism and its relationship with coronary artery disease in ethnic Kashmiri population. Clin Exp Med 2016; 16:551-556.

27. Miller J, Schwarz W. Aggregate and individual replication probability within an explicit model of the research process. Psychol Methods 2011;16:337-360.

28. Karahan Z, Uğurlu M, Uçaman B, Uluğ AV, Kaya İ, Çevik K, Öztürk Ö, Iyem H. Relation between apolipoprotein E gene polymorphism and severity of coronary artery disease in acute myocardial infarction. Cardiol Res Pract 2015;2015:363458.

29. Miyata M, Smith JD. Apolipoprotein E allele–specific antioxidant activity and effects on cytotoxicity by oxidative insults and β–amyloid peptides. Nat Genet 1996;14:55-61.

30. Tudorache IF, Trusca VG, Gafencu AV. Apolipoprotein E-a multifunctional protein with implications in various pathologies as a result of its structural features. Comput Struct Biotechnol J 2017;15:359-365.

31. Ghaznavi H, Mahmoodi K, Soltanpour MS. A preliminary study of the association between the ABCA1 gene promoter DNA methylation and coronary artery disease risk. Mol Biol Res Commun 2018;7:59-65.

32. Muka T, Koromani F, Portilla E, O'Connor A, Bramer WM, Troup J, Chowdhury R, Dehghan A, Franco OH. The role of epigenetic modifications in cardiovascular disease: A systematic review. Int J Cardiol 2016;212:174-183.