ASSOCIATION ANALYSIS OF POLYMORPHISM IN MODIFYING GENES FOR BLOOD PRESSURE AND GENES FOR IMMUNE RESPONSE REGULATION WITH ISCHEMIC HEART DISEASE

DOI: https://doi.org/None

A.N. Kucher (1,2), S.V. Buikin (1), N.P. Babuschkina (1), K.V. Puzyrev (1), A.A. Garganeeva (3), V.M. Schipulin (3), V.P. Puzyrev (1) 1 -Research institute of medical genetics of Siberian branch of the RAMS, Naberezhnaja reki Uschayki, 10, Tomsk, 634050, Russian Federation; 2 -Tomsk State University, Lenina prospect, 36, Tomsk, 634050, Russian Federation; 3 -Research institute of cardiology of Siberian branch of the RAMS, Kievskaja street, 111a, Tomsk, 634012, Russian Federation

Introduction. Genetic predispose to ischemic heart disease (CHD) are the priority directions in the study of etiological factors this condition. The aim of the study. Association analysis of polymorphism in modifying genes for blood pressure and genes for immune response regulation with ischemic heart disease Methods. Using PCR-RFLP analysis we studied 22 functional SNP in 15 genes (ADRB2, NOS3, ACE, AGTR1, GNB3, IL4, IL4R, IL12A, IL12B, IL12RB1, LTA, TNF, TNFRSF1В, IFNG и IFNGR2) in ischemic heart disease patients. Results. Genotypes TT of rs4291 in ACE, (OR=5,26), GG of rs1061622 in TNFRSF1B (OR=6,63) (recessive model) and СТ и ТТ of rs5443 in GNB3 (OR=1,80) (additive model) have risk effect for ischemic heart disease. Combinations of genotypes TT (rs4291) and GG (rs4343) in ACE (OR=5,94), AG (rs909253) in LTA and GG (rs1800629) in TNF (OR=2,37) are predisposing for IHD; CC (rs3746190) and AG (rs11575926) in IL12RB1 (OR=0,11), CC(rs2070744) and AB(VNTR) in NOS3 (OR=0,34) are protective for IHD. Conclusion. Associations with the disease were detected for allele and genotype frequencies of rs4291 (АСЕ), rs1061622 (TNFRSF1B) и rs5443 (GNB3), combinations of genotypes for genes АСЕ, NOS3, TNF/LTA, IL12RB1 and for haplotype frequencies of TNF/LTA.
Keywords: 
genetic polymorphism, cardiovascular disease, ischemic heart disease
Список литературы: 
  1. Sayols-Baixeras S, Lluis-Ganella C, Lucas G, Elosua R Pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants, Appl. Clin. Genet. 2014; 167:15–32.
  2. http://geneticassociationdb.nih.gov/cgi-bin/index.cgi
  3. http://www.hugenavigator.net/
  4. Zhang M-X, Ou H, Shen YH et al. Regulation of endothelial nitric oxide synthase by small RNA, PNAS. 2005; 102: 16967–72.
  5. Kucher A.N, Babushkina N.P., Markova V.V., Polovkova O.G., Zheykova T.V., An A.R., Nazarenko M.S., Botkina O.Yu., Bragina E.Yu., Golubenko M.V., Eremina E.R., Puzyrev V.P. Izmenchivost` polimorfnyh variantov genov-kandidatov zabolevaniy serdechno-sosudistoy sistemy u predstaviteley chetyreh e`tnicheskih grupp sibirskogo regiona. Medicinskaya genetika. 2010; 5: 24–34. [Kucher A.N., Babushkina N.P., Markova V.V., Polovkova O.G., Zheykova T.V., An A.R., Nazarenko M.S., Botkina O.Y., Bragina E.Y., Golubenko M.V., Eremina E.R., Puzyrev V.P. Genetic variation in the candidate genes for cardiovascular diseases in representatives of four ethnic groups from Siberia. Medicinskaja genetika. 2010; 5: 24–34 (in Russian)]
  6. Kucher A.N, Babushkina N.P., Tarasenko N.V. Golubenko M.V., Nazarenko M.S., Koneva L.A., Eremina E.R., Puzyrev V.P. Izmenchivost` polimorfnyh variantov genov faktorov nekroza opuholi i ih receptorov u predstaviteley chetyreh e`tnicheskih grupp sibirskogo regiona. Medicinskaya genetika. 2010; 6: 16–23. [Kucher A.N., Babushkina N.P., Tarasenko N.V., Golubenko M.V., Nazarenko M.S., Koneva L.A., Eremina E.R., Puzyrev V.P. Genetic variability in the genes of tumor necrosis factors and their receptors in four ethnic groups from Siberia. Medicinskaja genetika. 2010; 6: 16–23 (in Russian)]
  7. Kucher A.N., Babushkina N.P., Bragina E.Yu., An A.R., Rudko A.A., Freydin M.B., Puzyrev V.P. Izmenchivost` polimorfnyh variantov genov interleykinov i ih receptorov u predstaviteley chetyreh e`tnicheskih grupp sibirskogo regiona. Medicinskaya genetika. 2009; 10: 43–52. [Kucher A.N., Babushkina N.P., Bragina E.Y., An A.R., Rudko A.A., Freidin M.B., Puzyrev V.P. Variability of the interleukin ligand and receptor gene polymorphisms in four ethnic groups from Siberia. Medicinskaja genetika. 2009; 10: 43–52 (in Russian)]
  8. Goncharova I.A., Gamal` Abd El`-Aziz Nasr X., Beloborodova E.V., Ozhegova D.S., Stepanov V.A., Puzyrev V.P. Polimorfizm genov-modifikatorov immunnogo otveta pri zabolevaniyah pecheni razlichnoy e`tiologii. Medicinskaya genetika. 2010; 12: 20–4. [Goncharova I.A., Gamal Abd El-Aziz Nasr H., Beloborodova E.V., Ozhegova D.S., Stepanov V.A., Puzyrev V.P. Polymorphism of gene modifiers of immune response in liver diseases of different etiologies. Medicinskaja genetika. 2010; 12: 20–4 (in Russian)]
  9. Morris JA, Gardner MJ Calculating confidence intervals for relative risk (odds ratios) and standardized ratios and rates, British. Med. J. 1988; 296: 1313–6.
  10. Hill W.G. Estimation of linkage disequilibrium in randomly mating populations, Heredity. 1974; 33 (2): 229–39.
  11. Zhivotovskiy L.A. Populyacionnaya biometriya. M., Nauka; 1991. [Zhivotovskij L.A. Population biometrics. M., Nauka; 1991(in Russian)]
  12. Chung C.M., Wang R.Y., Fann C.S. et al. Fine-mapping angiotensin-converting enzyme gene: separate QTLs identified for hypertension and for ACE activity, PLoS One. 2013; 8 (3): e56119. doi:10.1371/journal.pone.0056119. Epub 2013 Mar 4.
  13. Miyamoto Y., Saito Y., Nakayama M. et al. Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a –786T C mutation associated with coronary spastic angina. Hum. Mol. Genet. 2000; 9: 2629–37.
  14. Song J., Yoon Y., Park K.U. et al. Genotype-specific influence on nitric oxide synthase gene expression, protien concentration, and enzyme activity in cultured human endotelial cells. Clin. Chem. 2003; 49: 847–52.
  15. Ozaki K., Ohnishi Y., Iida A. et al. Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 2002; 32: 650–4.
  16. Wilson A.G., Symons J.A., McDowell T.L. et al. Effects of a polymorphism in the human tumour necrosis factor alpha promoter on transcriptional activation. PNAS. 1997; 94: 3195–9.
  17. http://www.ncbi.nlm.nih.gov/gene/7133
  18. Sun Z., Runne C., Tang X., Lin F. et al. The Gβ3 splice variant associated with the C825T gene polymorphism is an unstable and functionally inactive protein. Cell. Signal. 2012; 24 (12): 2349–59.
  19. Casas J.P., Bautista L.E., Humphries S.E. et al. Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects. Circulation. 2004; 109: 1359–65.
  20. Abdel-Aziz T.A., Mohamed R.H. Association of endothelial nitric oxide synthase gene polymorphisms with classical risk factors in development of premature coronary artery disease Mol. Biol. Rep. 2013; 40 (4): 3065–71.
  21. Narne P., Ponnaluri K.C., Singh S. et al. Association of the genetic variants of endothelial nitric oxide synthase gene with angiographically defined coronary artery disease and myocardial infarction in South Indian patients with type 2 diabetes mellitus. J. Diabet. Compl. 2013; 27 (3): 255–61.
  22. Zigra A.M., Rallidis L.S., Anastasiou G. et al. eNOS gene variants and the risk of premature myocardial infarction. Dis. Markers. 2013; 34 (6): 431–6.
  23. Liu C.S., Huang R.J., Sung F.C. et al. Association between endothelial nitric oxide synthase polymorphisms and risk of metabolic syndrome. Dis. Markers. 2013; 34 (3): 187–97.
  24. Ekmekçi A., Ozcan K.S., Güngör B. et al. The relationship between endothelial nitric oxide synthase 4a/4b gene polymorphism and premature coronary artery disease. Acta Cardiol. 2013; 68 (5): 464–8.
  25. Chistyakov D.A., Voron’ko O.E., Savostyanov K.V., Minushkina L.O., Zateischikov D.A., Nosikov V.V. Polymorphic markers at the genes encoding the endothelial NO-synthase and angiotensin II type 1 receptor and the susceptibility to ischemic heart disease. Russian J. of Genetics. 2000; 36 (12): 1440–4.
  26. Nikitin A.G., Chudakova D.A., Spitsina E.V., Nosikov V.V., Debabov V.G., Minushkina L.O., Zateishchikov D.A. Association of GNB3 gene C825T polymorphism with coronary heart disease. Russian J. of Genetics. 2007; 43 (8): 937–41.
  27. Khamidullaeva G.A., Eliseyeva M.R., Nagay A.V. et al. C825T polymorphism of the G-protein β3 subunit and its association with essential hypertension in Uzbek males, Turk. Kardiyol. Dern. Ars. 2011; 3 (39): 198–204.
  28. Siffert W. G. protein β3 subunit 852 allele, hypertension, obesity, and diabetic nephropathy. Nephrol. Dial. Transplant. – 2000; 15: 1297–306.
  29. Siffert W., Naber C., Walla M., Ritz E. G protein β3 subunit 852T allele and its potential association with obesity in hypertensive individuals. J. Hypertens. 1999; 17: 1–4.
  30. Banas A., Plonska E., Larysz B. et al. Influence of 825 C>T polymorphism of G protein β3 subunit gene (GNB3) on hemodynamic response during dobutamine stress echocardiography. Pharmacol. Rep. 2012; 64 (1): 123–8.
  31. Casiglia E., Tikhonoff V., Boschetti G. et al. The C825T GNB3 polymorphism, independent of blood pressure, predicts cerebrovascular risk at a population level. Am. J. Hypertens. 2012; 4 (25): 451–7.
  32. Minushkina L.O., Nikitin A.G., Brazhnik V.A., Nosikov V.V., Zateyshhikov D.A. Izuchenie associacii polimorfizma genov b-adrenoreceptorov s urovnem arterial`nogo davleniya i razvitiem gipertrofii miokarda u bol`nyh gipertonicheskoy bolezn`yu. Rossiyskiy medicinskiy zhurnal. 2010; 5: 11–6. [Minushkina L.O., Nikitin A.G., Brazhnik V.A., Nosikov V.V., Zatejshhikov D.A. Association study of b-adrenoceptors gene polymorphism with level of arterial blood pressure and myocardial hypertrophy development in hypertension patients. Rossijskij medicinskij zhurnal. 2010; 5: 11–6 (in Russian)]
  33. Kajanatie E., Rautanen F., Kere J. et al. The effects of the ACE gene inserion/deletion polymorphism on glucose tolerance and insulin secretion in elderly people are modified by birth weight. J. Clin. Endocr. Metab. 2004; 89: 5738–41.
  34. Chugunova D.N. Geneticheskie osobennosti formirovaniya sutochnogo profilya arterial`nogo davleniya. Prakticheskaya medicina. 2010; 44: 127–9. [Chugunova D.N. Genetic characteristics of daily profile of arterial blood pressure. Prakticheskaja medicina. 2010; 44: 127–9 (in Russian)]
  35. Gubaev K.I., Nasibullin T.R., Mustafina O.E., Zakirova A.N. Association of polymorphic markers I/D of gene ACE and A1166C of gene AT2R1 with ischemic chronic heart failure in the Russian and Tatar populations of Bashkortostan Republic. Russian Journal of Genetics. 2006; 12 (42): 1447–51.
  36. Puzyrev V.P., Freydin M.B., Kucher A.N. Geneticheskoe raznoobrazie narodonaseleniya i bolezni cheloveka. Tomsk, Pechatnaya manufaktura; 2007. [Puzyrev V.P., Frejdin M.B., Kucher A.N. Population genetic variability and human diseases. Tomsk, Pechatnaja manufaktura; 2007 (in Russian)]
  37. Glenn C.L., Wang W.Y., Benjafield A.V. et al. Linkage and association of tumor necrosis factor receptor 2 locus with hypertension, hypercholesterolemia and plasma shed receptor. Hum. Mol. Genet. 2000; 9: 1943–9.
  38. Tabassum R., Chavali S., Mahajan A. et al. Association analysis of TNFRSF1B polymorphisms with type 2 diabetes and its related traits in North India. Genomic. Med. 2008; 2 (3–4): 93–100.
  39. Sbarsi I., Falcone C., Boiocchi C. et al. Inflammation and atherosclerosis: the role of TNF and TNF receptors polymorphisms in coronary artery disease. Int. J. Immunopathol. Pharmacol. 2007; 20 (1): 145–54.
  40. Sookoian S., Garcií S.I., Gianotti T.F. et al. The G-308A Promoter Variant of the Tumor Necrosis Factor-α Gene Is Associated With Hypertension in Adolescents Harboring the Metabolic Syndrome. Am. J. Hypertens. 2005; 18: 1271–5.
  41. Zateyshhikov D.A., Pushkov A.A., Nikitin A.G., Brovkin A.N., Evdokimova M.A., Baklanova T.N., Tereshhenko S.N., Dzhaiani N.A., Akatova E.V., Glezer M.G., Galyavich A.S., Koziolova N.A., Yagoda A.V., Boeva O.I., Horolec E.V., Shlyk S.V., Volkova E`.G., Konstantinov V.O., Nosikov V.V. Associaciya genov TNF i LTA s oslozhneniyami ateroskleroza u bol`nyh, perenesshih obostrenie ishemicheskoy bolezni serdca. Klinicheskaya praktika. 2013; 1 (13): 4–11. [Zateyshchikov D.A., Pushkov A.A., Nikitin A.G., Brovkin A.N., Evdokimova M.A., Baklanova T.N., Tereschenko S.N., Dzhaiani N.A., Akatova E.V., Glezer M.G., Galyavich A.S., Koziolova N.A., Yagoda A.V., Boyeva O.I., Horolets E.V., Shlyk S.V., Volkova E.G., Konstantinov V.O., Nosikov V.V., Blagodatskih K.A. Association of TNF and LTA genes with atherosclerosis complications in patients with history of acute coronary syndrome. Klinicheskaja praktika. 2013; 1 (13): 4–11 (in Russian)]
  42. Timasheva Ya.R., Nasibullin T.R., Tuktarova I.A. Analiz mezhgennyh vzaimodeystviy polimorfnyh lokusov genov citokinov u bol`nyh e`ssencial`noy gipertenziey. Arterial`naya gipertenziya. 2012; 18 (5): 443–8. [Timasheva Y.R., Nasibullin T.R., Tuktarova I.A., Karamova I.M., Petrin A.N., Mustafina O.E. Analysis of gene-gene interactions of polymorphic cytokine genes loci in hypertension patients. Arterial’naja gipertenzija. 2012; 18 (5): 443–8 (in Russian)]
  43. Sudomoina M.A., Sukhinina T.S., Barsova R.M., Sakhnovich R.M., Titov B.V., Matveeva N.A., Rybalkin I.N., Vlasik T.N., Ruda M.Y., Favorova O.O., Favorov A.V., Ochs M.F. Complex analysis of association of inflammation gene polymorphisms with myocardial infarction. Molecular Biology. 2010; 44 (3): 407–14.
  44. Arlestig L., Wållberg J.S., Stegmayr B. et al. Polymorphism of genes related to cardiovascular disease in patients with rheumatoid arthritis, Clin. Exp. Rheumatol. 2007; 25 (6): 866–71.