medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.1234/XXXX-XXXX-2016-6-11-18medgen-137Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHРоль полиморфных вариантов гена ангиотензин-превращающего фермента (АСЕ) в формировании различных типов ремоделирования миокарда у больных хронической сердечной недостаточностьюRole of polymorphic variants of angiotensin-converting gene (ACE) in heart failure developmentПушкареваА. Э.PushkarevaA. E.noemail@neicon.ruХусаиноваР. И.KhusainovaR. I.noemail@neicon.ruВалиевР. Р.ValievR. R.noemail@neicon.ruАрутюновГ. П.ArutyunovG. P.noemail@neicon.ruХуснутдиноваЭ. К.KhusnutdinovaE. K.ekkh@anrb.ruИнститут биохимии и генетики Уфимского научного центра Российской академии наукРоссияBachkir State Medical University; Institute of Biochemistry and Genetics of Ufa Sciense Centre RASRussian FederationИнститут биохимии и генетики Уфимского научного центра Российской академии наукРоссияInstitute of Biochemistry and Genetics of Ufa Sciense Centre RASRussian FederationРоссийский национальный исследовательский университет им. Н.И. ПироговаРоссияPirogov Russian National Research Medical UniversityRussian Federation2016071020161561118Copyright © Пушкарева А.Э., Хусаинова Р.И., Валиев Р.Р., Арутюнов Г.П., Хуснутдинова Э.К., 20162016Пушкарева А.Э., Хусаинова Р.И., Валиев Р.Р., Арутюнов Г.П., Хуснутдинова Э.К.Pushkareva A.E., Khusainova R.I., Valiev R.R., Arutyunov G.P., Khusnutdinova E.K.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/137

Хроническая сердечная недостаточность (ХСН) является одной из лидирующих причин инвалидизации и смертности населения. Учитывая важную роль нейроэндокринных систем в развитии ХСН, актуальным подходом является изучение полиморфизма генов, продукты экспрессии которых участвуют в формировании различных типов ремоделирования миокарда и прогрессировании ХСН . Проведено изучение трех полиморфных локусов гена ACE - rs4343 (2350 G>А) , rs4291 (240A>T), rs4340 (I/D) у 271 пациента с ХСН (II-IV ФК) с различными типами ремоделирования левого желудочка (ЛЖ) и 194 условно здоровых мужчин и женщин соответствующего возраста, а также гаплотипов изученных полиморфных локусов гена АСЕ . Значимыми в развитии ХСН и различных типов ремоделирования миокарда ЛЖ являются гомозиготные генотипы *G*G локуса rs4343 и *D*D локуса rs4340, а также гаплотип на основе этих двух локусов *DG гена ACE . При рассмотрении гаплотипов всех трех полиморфных локусов ACE ( rs4291 , rs4340 и rs4343 ) преобладание гаплотипа *TDG было статистически значимым у больных с выраженной гипертрофией ЛЖ и умеренной гипертрофией ЛЖ.

Chronic heart failure (CHF) is one of the high-end causes of populations disability and mortality. Considering the fundamental role of neurohormonal systems in CHF development, the current approach is the study of genes, what expression products take part in formation of different types for myocardial remodeling and CHF progression. Three polymorphic loci in ACE gene- rs4343 (2350 G>А) , rs4291 (240A>T), rs4340 (I/D) in 271 patient of CHF (functional class II-IV) with different types of the left ventricle (LV) remodeling and 194 conditionally healthy men and women of corresponding age, also their haplotypes were studied. Homozygous genotypes *G*G locus rs4343 and *D*D locus rs4340 , also haplotype, based on these two loci, *DG gene ACE , are significant for CHF developing and remodeling LV, considering different types. By revising haplotypes for all three polymorphic loci of ACE gene (rs4291 , rs4340 and rs4343 ), the predominance of haplotype *TDG was statistically significant for patients with marked hypertrophy LV and moderate hypertrophy LV.

ремоделирование левого желудочкаХСНген ангиотензин-превращающего фермента (АСЕ)полиморфный локусгенотипгаплотипremodeling of the left ventriclechronic heart failure (CHF)angiotensin-converting enzyme gene (ACE)polymorphic locusgenotypehaplotypeReferencesGreenberg B. An ACE in the hole: Alternative Pathways of the Renin Angiotensin System and Their Potential Role in Cardiac Remodeling // J. Am. Coll. Cardiol. - 2008. - Vol. 52. - P. 755-757.Greenberg B. An ACE in the hole: Alternative Pathways of the Renin Angiotensin System and Their Potential Role in Cardiac Remodeling // J. Am. Coll. Cardiol. - 2008. - Vol. 52. - P. 755-757.Der Sarkissan S., Huentelman M.J., Sterwart J., Katovich M.J., Raizada M.K. ACE2: A novel therapeutic target for cardiovascular diseases // Prog. Biophys. Mol. Biol. - 2006. - May-Jun. - Vol. 91(1-2). - P. 163-198.Der Sarkissan S., Huentelman M.J., Sterwart J., Katovich M.J., Raizada M.K. ACE2: A novel therapeutic target for cardiovascular diseases // Prog. Biophys. Mol. Biol. - 2006. - May-Jun. - Vol. 91(1-2). - P. 163-198.Wang Yazhu, Li Ying, Fan Jinqi et al. Association study of the angiotensin-converting enzyme (ACE) gene rs4340 and rs4343 polymorphism with atrial fibrillation // Heart. - 2011. - Vol. 97. - A57 doi:10.1136/heartjnl-2011-300867.168.Wang Yazhu, Li Ying, Fan Jinqi et al. Association study of the angiotensin-converting enzyme (ACE) gene rs4340 and rs4343 polymorphism with atrial fibrillation // Heart. - 2011. - Vol. 97. - A57 doi:10.1136/heartjnl-2011-300867.168.Liza U Ljungberg, Carl Johan Ostgren, Fredrik H Nystrom et al. Associations of genetic polymorphisms in the renin-angiotensin system with central aortic and ambulatory blood pressure in type 2 diabetic patients. Journal of Renin-Angiotensin-Aldosteron System published online 28 January 2013. http://jra.sagepub.com/content/early/2013/ 01/28/1470320312474052Liza U Ljungberg, Carl Johan Ostgren, Fredrik H Nystrom et al. Associations of genetic polymorphisms in the renin-angiotensin system with central aortic and ambulatory blood pressure in type 2 diabetic patients. Journal of Renin-Angiotensin-Aldosteron System published online 28 January 2013. http://jra.sagepub.com/content/early/2013/ 01/28/1470320312474052Rudnicki M., Mayer G. Significance of genetic polymorphisms of the renin-angiotensin-aldosterone system in cardiovascular and renal disease // Pharmacogenomics. - 2009. - 10. - P. 463-476.Rudnicki M., Mayer G. Significance of genetic polymorphisms of the renin-angiotensin-aldosterone system in cardiovascular and renal disease // Pharmacogenomics. - 2009. - 10. - P. 463-476.Fatini Cinzia MD, PhD; Sticchi, Elena BS, Marcucci, Rossalla MD, PhD et al. ACE Insertion/Deletion, but not -240A>T polymorphism, modulate the severity in heart failure // Journal of Investigative Medicine. - 2008. - December. - Vol. 56. - Issue 8. - P. 1004-1010.Fatini Cinzia MD, PhD; Sticchi, Elena BS, Marcucci, Rossalla MD, PhD et al. ACE Insertion/Deletion, but not -240A>T polymorphism, modulate the severity in heart failure // Journal of Investigative Medicine. - 2008. - December. - Vol. 56. - Issue 8. - P. 1004-1010.Marcin Zakrzewski-Jakubiak, Simon de Denus, Marie-Pierre Dube et al. Ten renin-angiotensin system-related gene polymorphisms in maximally treated Canadian Cacausian patients with heart failure // Br. J. Clin. Pharmacol. - 2008. - 65:5. - P. 742-751.Marcin Zakrzewski-Jakubiak, Simon de Denus, Marie-Pierre Dube et al. Ten renin-angiotensin system-related gene polymorphisms in maximally treated Canadian Cacausian patients with heart failure // Br. J. Clin. Pharmacol. - 2008. - 65:5. - P. 742-751.En-Zhi Jia, Zhen-Xia Xu, Chang-Yan Guo et al. Renin-angiotensin-aldosterone polymorphisms and coronary artery disease: detection of gene-gene and gene-environment interactions // Cell Physiology and Biochemistry. - 2012. - Vol. 29. - P. 443-452.En-Zhi Jia, Zhen-Xia Xu, Chang-Yan Guo et al. Renin-angiotensin-aldosterone polymorphisms and coronary artery disease: detection of gene-gene and gene-environment interactions // Cell Physiology and Biochemistry. - 2012. - Vol. 29. - P. 443-452.QIU Chunguang, HAN Zhanying, LU Wenjie, ZHANG Cuntai. Association of polymorphisms in angiotensin-converting enzyme and type1 angiotensinII receptor genes with coronary heart disease and severity of coronary artery stenosis // Journal of Huazhong University and Techology. - 2007. - Vol. 27(6). - P. 660-663.QIU Chunguang, HAN Zhanying, LU Wenjie, ZHANG Cuntai. Association of polymorphisms in angiotensin-converting enzyme and type1 angiotensinII receptor genes with coronary heart disease and severity of coronary artery stenosis // Journal of Huazhong University and Techology. - 2007. - Vol. 27(6). - P. 660-663.Frank G.A. De Bakker, Peter Groenewegen, Frank Den Hond. A Bibliometric Analysis of 30 Years of Research and Theory on Corporate Social Responsibility and Corporate Social Performance // Business & Society. - 2005. - Vol. 44(3). - P. 283-317.Frank G.A. De Bakker, Peter Groenewegen, Frank Den Hond. A Bibliometric Analysis of 30 Years of Research and Theory on Corporate Social Responsibility and Corporate Social Performance // Business & Society. - 2005. - Vol. 44(3). - P. 283-317.Crawford D.C., Akey D.T., Nickersson D.A. The patterns of natural variation in human genes // Annu Rev Genomics Hum Genet. - 2005. - 6. - P. 287-312.Crawford D.C., Akey D.T., Nickersson D.A. The patterns of natural variation in human genes // Annu Rev Genomics Hum Genet. - 2005. - 6. - P. 287-312.Bin Zhang and Steve Horvath. Statistical applications in genetics and molecular biology. Volume 4, Issue 1. 2005. Article 17. Department of Human Genetics and Biostatistcs, University of California at Los Angeles.Bin Zhang and Steve Horvath. Statistical applications in genetics and molecular biology. Volume 4, Issue 1. 2005. Article 17. Department of Human Genetics and Biostatistcs, University of California at Los Angeles.Slatkin M. Linkage disequilibrium- understanding the evolutionary past and mapping the medical future // Nat. Rev. Genet. - 2008. - Jun. - 9(6). - P. 477-485.Slatkin M. Linkage disequilibrium- understanding the evolutionary past and mapping the medical future // Nat. Rev. Genet. - 2008. - Jun. - 9(6). - P. 477-485.Levenstein M.A., Ott J., Gordon D. Are molecular haplotypes worth the time and expense? A cost-effective method for applying molecular haplotypes // PLoS Genet. - 2006. - 2.Levenstein M.A., Ott J., Gordon D. Are molecular haplotypes worth the time and expense? A cost-effective method for applying molecular haplotypes // PLoS Genet. - 2006. - 2.Мареев В.Ю., Агеев Ф.Т., Арутюнов Г.П. и др. Национальные рекомендации ВНОК и ОССН по диагностике и лечению ХСН (III пересмотр) // Сердечная недостаточность. - 2010. - №1(57).Мареев В.Ю., Агеев Ф.Т., Арутюнов Г.П. и др. Национальные рекомендации ВНОК и ОССН по диагностике и лечению ХСН (III пересмотр) // Сердечная недостаточность. - 2010. - №1(57).Функциональная диагностика в кардиологии: клиническая интерпретация: Учебное пособие / Под ред. Васюка Ю.А. - М.: Практическая медицина, 2009. - 312 с.Функциональная диагностика в кардиологии: клиническая интерпретация: Учебное пособие / Под ред. Васюка Ю.А. - М.: Практическая медицина, 2009. - 312 с.Hsieh Y.Y., Chang C.C., Tsai F.J., Hsu C.M., Lin C.C., Tsai C.H. Angiotensin I-converting enzyme ACE2350*G and ACE-240*T-related genotypes and alleles are associated with higher susceptibility to endometriosis // Mol. Hum. Reprod. - 2005. - Jan;(1). - P. 11-14.Hsieh Y.Y., Chang C.C., Tsai F.J., Hsu C.M., Lin C.C., Tsai C.H. Angiotensin I-converting enzyme ACE2350*G and ACE-240*T-related genotypes and alleles are associated with higher susceptibility to endometriosis // Mol. Hum. Reprod. - 2005. - Jan;(1). - P. 11-14.Iwai N., Ohmichi N., Nakamura Y., Kinoshita M. DD genotype of the angiotensin-converting enzyme gene is a risk factor for left ventricular hypertrophy // Circulation. - 1994. - Dec. - Vol. 90(6). - P. 2622-2628.Iwai N., Ohmichi N., Nakamura Y., Kinoshita M. DD genotype of the angiotensin-converting enzyme gene is a risk factor for left ventricular hypertrophy // Circulation. - 1994. - Dec. - Vol. 90(6). - P. 2622-2628.Barrett J.C., Fry B., Maller J., Daly M.J. Haploview: analysis and visualization of LD and haplotype maps // Bioinformatics. - 2005. - 21(2). - P. 263-265.Barrett J.C., Fry B., Maller J., Daly M.J. Haploview: analysis and visualization of LD and haplotype maps // Bioinformatics. - 2005. - 21(2). - P. 263-265.McNamara D.M. Pharmocogenetics in Heart Failure: Genomic markers of endothelial and neurohumoral function // Congestive Heart Failure. - 2004. - 10. - P. 302-308.McNamara D.M. Pharmocogenetics in Heart Failure: Genomic markers of endothelial and neurohumoral function // Congestive Heart Failure. - 2004. - 10. - P. 302-308.Marzia Rigolli, Mariantonietta Cicoira, Corinna Bergamini et al. Progression of left ventricular dysfunction and remodelling under optimal medical therapy in CHF patients: role of individual genetic background // Cardiology Research and Practice. - 2011. - Vol. 2011; Article ID 798658Marzia Rigolli, Mariantonietta Cicoira, Corinna Bergamini et al. Progression of left ventricular dysfunction and remodelling under optimal medical therapy in CHF patients: role of individual genetic background // Cardiology Research and Practice. - 2011. - Vol. 2011; Article ID 798658Haixin Lei, Ian N.M. Day, Igor Vorechovsky. Exonization of AluYa5 in human ACE gene requires mutations in both 3/ and 5/ splice sites and it facilitated by a conserved splicing enhancer // Nucleic Acids Res. - 2005. - Vol. 33(12). - P. 3897-3906.Haixin Lei, Ian N.M. Day, Igor Vorechovsky. Exonization of AluYa5 in human ACE gene requires mutations in both 3/ and 5/ splice sites and it facilitated by a conserved splicing enhancer // Nucleic Acids Res. - 2005. - Vol. 33(12). - P. 3897-3906.Воевода М.И., Степанов В.А., Ромащенко А.Т., Максимов В.Н. Этногенетические особенности подверженности атеросклерозу в этнических группах Сибири на примере аполипопротеина Е // Бюллетень СО РАМН. - 2006. - №2(120). - С. 63-72.Воевода М.И., Степанов В.А., Ромащенко А.Т., Максимов В.Н. Этногенетические особенности подверженности атеросклерозу в этнических группах Сибири на примере аполипопротеина Е // Бюллетень СО РАМН. - 2006. - №2(120). - С. 63-72.Ana I Freitas, Isabel Mendonca, Maria Brion et al. RAS gene polymorphisms, classical risk factors and the advent of coronary artery disease in Portuguese population // BMC Cardiovascular Disordes. - 2008. - 8. - 15.Ana I Freitas, Isabel Mendonca, Maria Brion et al. RAS gene polymorphisms, classical risk factors and the advent of coronary artery disease in Portuguese population // BMC Cardiovascular Disordes. - 2008. - 8. - 15.Nancy Martinez-Rodriquez, Carios Posadas-Romero, Teresa Villarreal-Molina et al. Single Nucleotide Polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with essential hypertension and increased ACE enzyme levels in Mexican individuals // PloS One. - 2013. - 8(5). - e65700.Nancy Martinez-Rodriquez, Carios Posadas-Romero, Teresa Villarreal-Molina et al. Single Nucleotide Polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with essential hypertension and increased ACE enzyme levels in Mexican individuals // PloS One. - 2013. - 8(5). - e65700.Paolo Catarsi, Roberto Ravazzolo, Francesco Emma et al. Angiotensin-converting enzyme (ACE) haplotypes and cydosporine A(CsA) response: a model of the complex relationship between ACE quantitave trait locus and pathological phenotypes // Hum. Mol. Genet. 2005. - Aug 7. - Vol. 14(16). - P. 2357-2367.Paolo Catarsi, Roberto Ravazzolo, Francesco Emma et al. Angiotensin-converting enzyme (ACE) haplotypes and cydosporine A(CsA) response: a model of the complex relationship between ACE quantitave trait locus and pathological phenotypes // Hum. Mol. Genet. 2005. - Aug 7. - Vol. 14(16). - P. 2357-2367.

The authors declare that there are no conflicts of interest present.