medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.25557/2073-7998.2021.04.30-42medgen-1904Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHПолиморфизм гена IL6 (rs1800795) может быть ассоциирован с развитием патологии сердечно-сосудистой системы на фоне злоупотребления алкоголемIL6 rs1800795 SNP may relate to cardiovascular pathology in alcohol abusersПерегудД. И.PeregudD. I.peregud_d@yahoo.comБаронецВ. Ю.BaronetsV. Yu.noemail@neicon.ruЛобачеваА. С.LobachevaA. S.noemail@neicon.ruИвановА. С.IvanovA. S.noemail@neicon.ruГармашИ. В.GarmashI. V.noemail@neicon.ruАришеваО. С.ArishevaO. S.noemail@neicon.ruКобалаваЖ. Д.KobalavaZ. D.noemail@neicon.ruПирожковС. В.PirozhkovS. V.noemail@neicon.ruТеребилинаН. Н.TerebilinaN. N.noemail@neicon.ruНациональный научный центр наркологии - филиал Федерального государственного бюджетного учреждения «Национальный медицинский исследовательский центр психиатрии и наркологии им. В.П. Сербского» Министерства здравоохранения Российской ФедерацииРоссияV. Serbsky National Medical Research Center for Psychiatry and Drug Addiction of the Ministry of Health of the Russian FederationRussian FederationФГАОУ ВО «Российский университет дружбы народов»РоссияPeoples’ Friendship University of RussiaRussian FederationФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» (Сеченовский Университет) Минздрава РоссииРоссияI.M. Sechenov First Moscow State Medical University (Sechenov University) of the Ministry of Health of RussiaRussian Federation2021040820212043042Copyright © Перегуд Д.И., Баронец В.Ю., Лобачева А.С., Иванов А.С., Гармаш И.В., Аришева О.С., Кобалава Ж.Д., Пирожков С.В., Теребилина Н.Н., 20212021Перегуд Д.И., Баронец В.Ю., Лобачева А.С., Иванов А.С., Гармаш И.В., Аришева О.С., Кобалава Ж.Д., Пирожков С.В., Теребилина Н.Н.Peregud D.I., Baronets V.Y., Lobacheva A.S., Ivanov A.S., Garmash I.V., Arisheva O.S., Kobalava Z.D., Pirozhkov S.V., Terebilina N.N.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/1904

Формирование сердечно-сосудистой патологии при чрезмерном употреблении алкоголя сопряжено с повышением концентрации в крови таких медиаторов воспаления, как интерлейкины 6 (IL6) и 8 (IL8) и хемоаттрактанта моноцитов CCL2 (C-C motif ligand 2), а также молекул, участвующих в функционировании эндотелия, в частности фактора роста сосудистого эндотелия (VEGFA, vascular endothelial growth factor А), молекулы клеточной адгезии (ICAM1, intercellular adhesion molecule 1) и эндотелина (EDN1). Предполагается, что данный процесс генетически детерминирован, однако до настоящего момента исследований в этом направлении не проводилось. Целью работы явилось изучение ассоциации носительства аллелей полиморфных локусов, расположенных в генах IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 и rs2010963), ICAM1 (rs281437) и EDN1 (rs1800541) с содержанием соответствующих полипептидов в циркуляторном русле и развитием сердечно-сосудистых заболеваний на фоне хронического злоупотребления алкоголем. В исследование были включены лица, злоупотребляющие алкоголем, без выраженной соматической патологии, а также пациенты, у которых на фоне злоупотребления развились заболевания сердечно-сосудистой системы. Уровень IL6, IL8, CCL2, VEGFA, ICAM1 и EDN1 в сыворотке крови оценивали посредством ИФА. Аллели полиморфных локусов были определены посредством ПЦР в режиме реального времени. Установлено, что среди лиц, злоупотребляющих алкоголем, с клинически выраженной патологией сердечно-сосудистой системы значительно чаще встречаются только носители гомозиготного генотипа GG или аллеля G полиморфного локуса в гене IL6 (rs1800795). Кроме того, носительство генотипа GG повышает вероятность развития сердечно-сосудистых заболеваний при хроническом злоупотреблении алкоголем. Однако, дополнительное влияние оказывают демографические факторы и клинические характеристики пациентов. В частности, введение поправки на возраст и пол, а также учет наличия цирроза печени, гипертензии и сахарного диабета, сопровождающих злоупотребление алкоголем, нивелируют повышение риска патологии сердечно-сосудистой системы. Ассоциации полиморфных вариантов в генах IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 и rs2010963), ICAM1 (rs281437) и EDN1 (rs1800541) с содержанием белковых продуктов соответствующих генов в циркуляторном русле выявлено не было.

Cardiovascular diseases in alcohol abusers are associated with elevation of plasma levels of proinflammatory cytokines such as IL6, IL8 and CCL2 as well as molecules involved in endothelial functioning including VEGFA, ICAM1 and EDN1. This phenomenon is supposed to be genetically determined. However to date the issue has not been investigated. Thus, we aimed to study the relationship between carriage of SNPs of IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 and rs2010963), ICAM1 (rs281437) and EDN1 (rs1800541) genes with the serum levels of their products and the development of cardiovascular diseases in alcohol abusers. The study included alcohol abusers without apparent somatic pathology and alcohol abusers with clinical manifestations of cardiovascular disease. Serum levels of IL6, IL8, CCL2, VEGFA, ICAM1 and EDN1 were estimated by EIA. SNPs were determined by means of real-time PCR. We found that among the SNPs studied only carriers of homozygous GG genotype and G allele of IL6 (rs1800795) were more frequent in alcohol abusers with cardiovascular diseases. Moreover, carriage of homozygous GG genotype of IL6 (rs1800795) increases the probability of development of cardiovascular pathology in alcohol abusers. However, adjustment for age, gender and the presence of liver cirrhosis, hypertension and diabetes mellitus as co-variates eliminates the enhanced risk of cardiovascular pathology. Polymorphisms of IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 and rs2010963), ICAM1 (rs281437) and EDN1 (rs1800541) did not determine serum levels of the related polypeptides.

злоупотребление алкоголемпатологиясердечно-сосудистая системаполиморфизм IL6 rs1800795alcohol abusepathologycardiovascular systemIL6 rs1800795 SNPReferencesАксельрод А.С., Сиволап Ю.П., Сыркин А.Л. и др. Риск внезапной смерти пациентов с алкогольной зависимостью: насколько актуальна проблема? Жур. неврол. и психиатр. им. С.С.Корсакова. 2011; 111(11-2): 44-48.Аксельрод А.С., Сиволап Ю.П., Сыркин А.Л. и др. Риск внезапной смерти пациентов с алкогольной зависимостью: насколько актуальна проблема? Жур. неврол. и психиатр. им. С.С.Корсакова. 2011; 111(11-2): 44-48.Fernández-Solà J., Nicolás J.M., Oriola J. et al. Angiotensin-converting enzyme gene polymorphism is associated with vulnerability to alcoholic cardiomyopathy. Ann. Intern. Med. 2002; 137(5 Part 1): 321-326.Fernández-Solà J., Nicolás J.M., Oriola J. et al. Angiotensin-converting enzyme gene polymorphism is associated with vulnerability to alcoholic cardiomyopathy. Ann. Intern. Med. 2002; 137(5 Part 1): 321-326.Ware J.S., Amor-Salamanca A., Tayal U. et al. Genetic Etiology for Alcohol-Induced Cardiac Toxicity. J. Am. Coll. Cardiol. 2018; 71(20): 2293-2302.Ware J.S., Amor-Salamanca A., Tayal U. et al. Genetic Etiology for Alcohol-Induced Cardiac Toxicity. J. Am. Coll. Cardiol. 2018; 71(20): 2293-2302.Mehlig K., Strandhagen E., Svensson P.A. et al. CETP TaqIB genotype modifies the association between alcohol and coronary heart disease: the INTERGENE case-control study. Alcohol 2014; 48(7): 695-700.Mehlig K., Strandhagen E., Svensson P.A. et al. CETP TaqIB genotype modifies the association between alcohol and coronary heart disease: the INTERGENE case-control study. Alcohol 2014; 48(7): 695-700.Holmes M.V., Dale C.E., Zuccolo L. et al. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ 2014; 349: g4164. doi: 10.1136/bmj.g4164.Holmes M.V., Dale C.E., Zuccolo L. et al. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ 2014; 349: g4164. doi: 10.1136/bmj.g4164.Lucas D.L., Brown R.A., Wassef M., Giles T.D. Alcohol and the cardiovascular system: research challenges and opportunities. J. Am. Coll. Cardiol. 2005; 45(12): 1916-1924.Lucas D.L., Brown R.A., Wassef M., Giles T.D. Alcohol and the cardiovascular system: research challenges and opportunities. J. Am. Coll. Cardiol. 2005; 45(12): 1916-1924.Amin M.N., Siddiqui S.A., Ibrahim M. et al. Inflammatory cytokines in the pathogenesis of cardiovascular disease and cancer. SAGE Open Med. 2020; 8: 2050312120965752. doi: 10.1177/2050312120965752.Amin M.N., Siddiqui S.A., Ibrahim M. et al. Inflammatory cytokines in the pathogenesis of cardiovascular disease and cancer. SAGE Open Med. 2020; 8: 2050312120965752. doi: 10.1177/2050312120965752.Williams J.W., Huang L.H., Randolph G.J. Cytokine Circuits in Cardiovascular Disease. Immunity 2019; 50(4): 941-954.Williams J.W., Huang L.H., Randolph G.J. Cytokine Circuits in Cardiovascular Disease. Immunity 2019; 50(4): 941-954.Seta Y., Shan K., Bozkurt B. et al. Basic mechanisms in heart failure: the cytokine hypothesis. J. Cardiac Failure 1996; 2(3): 243-249.Seta Y., Shan K., Bozkurt B. et al. Basic mechanisms in heart failure: the cytokine hypothesis. J. Cardiac Failure 1996; 2(3): 243-249.Widmer R.J., Lerman A. Endothelial dysfunction and cardiovascular disease. Glob. Cardiol. Sci. Pract. 2014; 2014(3): 291-308.Widmer R.J., Lerman A. Endothelial dysfunction and cardiovascular disease. Glob. Cardiol. Sci. Pract. 2014; 2014(3): 291-308.Giannitsi S., Bougiakli M., Bechlioulis A., Naka K. Endothelial dysfunction and heart failure: A review of the existing bibliography with emphasis on flow mediated dilation. JRSM Cardiovasc. Dis. 2019; 8: 2048004019843047. doi: 10.1177/2048004019843047.Giannitsi S., Bougiakli M., Bechlioulis A., Naka K. Endothelial dysfunction and heart failure: A review of the existing bibliography with emphasis on flow mediated dilation. JRSM Cardiovasc. Dis. 2019; 8: 2048004019843047. doi: 10.1177/2048004019843047.Kliche S., Waltenberger J. VEGF receptor signaling and endothelial function. IUBMB Life 2001; 52(1-2): 61-66.Kliche S., Waltenberger J. VEGF receptor signaling and endothelial function. IUBMB Life 2001; 52(1-2): 61-66.Krieglstein C.F., Granger D.N. Adhesion molecules and their role in vascular disease. Am. J. Hypertens. 2001; 14(6 Pt 2): 44S-54S.Krieglstein C.F., Granger D.N. Adhesion molecules and their role in vascular disease. Am. J. Hypertens. 2001; 14(6 Pt 2): 44S-54S.Masaki T., Sawamura T. Endothelin and endothelial dysfunction. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2006; 82(1): 17-24.Masaki T., Sawamura T. Endothelin and endothelial dysfunction. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2006; 82(1): 17-24.Панченко Л.Ф., Моисеев В.С., Пирожков С.В. и др. Содержание маркеров воспаления и цитокинов в крови больных алкогольной кардиомиопатией и ишемической болезнью сердца на разных стадиях сердечной недостаточности. Кардиология 2015; 55(3): 41-48.Панченко Л.Ф., Моисеев В.С., Пирожков С.В. и др. Содержание маркеров воспаления и цитокинов в крови больных алкогольной кардиомиопатией и ишемической болезнью сердца на разных стадиях сердечной недостаточности. Кардиология 2015; 55(3): 41-48.Панченко Л.Ф., Пирожков С.В., Баронец В.Ю. и др. Содержание маркеров эндотелиалоьной дисфункции и медиаторов воспаления у больных алкоголизмом с хронической сердечной недостаточностью на конечных стадиях развития. Наркология 2018; (2): 20-28.Панченко Л.Ф., Пирожков С.В., Баронец В.Ю. и др. Содержание маркеров эндотелиалоьной дисфункции и медиаторов воспаления у больных алкоголизмом с хронической сердечной недостаточностью на конечных стадиях развития. Наркология 2018; (2): 20-28.Chen H., Ding S., Liu X. et al. Association of interleukin-6 genetic polymorphisms and Environment factors interactions with coronary artery disease in a Chinese Han population. Clin Exp. Hypertens. 2018; 40(6): 514-517.Chen H., Ding S., Liu X. et al. Association of interleukin-6 genetic polymorphisms and Environment factors interactions with coronary artery disease in a Chinese Han population. Clin Exp. Hypertens. 2018; 40(6): 514-517.Liaquat A., Asifa G.Z., Zeenat A., Javed Q. Polymorphisms of tumor necrosis factor-alpha and interleukin-6 gene and C-reactive protein profiles in patients with idiopathic dilated cardiomyopathy. Ann. Saudi Med. 2014; 34(5): 407-414.Liaquat A., Asifa G.Z., Zeenat A., Javed Q. Polymorphisms of tumor necrosis factor-alpha and interleukin-6 gene and C-reactive protein profiles in patients with idiopathic dilated cardiomyopathy. Ann. Saudi Med. 2014; 34(5): 407-414.Bielecka-Dabrowa A., Sakowicz A., Pietrucha T., et al. The profile of selected single nucleotide polymorphisms in patients with hypertension and heart failure with preserved and mid-range ejection fraction. Sci. Rep. 2017; 7(1): 8974. doi: 10.1038/s41598-017-09564-9Bielecka-Dabrowa A., Sakowicz A., Pietrucha T., et al. The profile of selected single nucleotide polymorphisms in patients with hypertension and heart failure with preserved and mid-range ejection fraction. Sci. Rep. 2017; 7(1): 8974. doi: 10.1038/s41598-017-09564-9Bennermo M., Held C., Green F. et al. Prognostic value of plasma interleukin-6 concentrations and the -174 G > C and -572 G > C promoter polymorphisms of the interleukin-6 gene in patients with acute myocardial infarction treated with thrombolysis. Atherosclerosis 2004; 174(1): 157-163.Bennermo M., Held C., Green F. et al. Prognostic value of plasma interleukin-6 concentrations and the -174 G > C and -572 G > C promoter polymorphisms of the interleukin-6 gene in patients with acute myocardial infarction treated with thrombolysis. Atherosclerosis 2004; 174(1): 157-163.Velásquez I.M., Frumento P., Johansson K. et al. Association of interleukin 8 with myocardial infarction: results from the Stockholm Heart Epidemiology Program. Int. J. Cardiol. 2014; 172(1): 173-178.Velásquez I.M., Frumento P., Johansson K. et al. Association of interleukin 8 with myocardial infarction: results from the Stockholm Heart Epidemiology Program. Int. J. Cardiol. 2014; 172(1): 173-178.Cai G., Zhang B., Weng W. et al. The associations between the MCP-1 -2518 A/G polymorphism and ischemic heart disease and ischemic stroke: a meta-analysis of 28 research studies involving 21,524 individuals. Mol. Biol. Rep. 2015; 42(5): 997-1012.Cai G., Zhang B., Weng W. et al. The associations between the MCP-1 -2518 A/G polymorphism and ischemic heart disease and ischemic stroke: a meta-analysis of 28 research studies involving 21,524 individuals. Mol. Biol. Rep. 2015; 42(5): 997-1012.Nasibullin T.R., Yagafarova L.F., Yagafarov I.R. et al. Combinations of polymorphic markers of chemokine genes, their receptors and acute phase protein genes as potential predictors of coronary heart diseases. Acta Naturae. 2016; 8(1): 111-116.Nasibullin T.R., Yagafarova L.F., Yagafarov I.R. et al. Combinations of polymorphic markers of chemokine genes, their receptors and acute phase protein genes as potential predictors of coronary heart diseases. Acta Naturae. 2016; 8(1): 111-116.Ogimoto A., Okayama H., Nagai T. et al. Association of monocyte chemoattractant protein 1 gene polymorphism with susceptibility to nonfamilial idiopathic dilated cardiomyopathy. J. Cardiol. 2009; 54(1): 66-70.Ogimoto A., Okayama H., Nagai T. et al. Association of monocyte chemoattractant protein 1 gene polymorphism with susceptibility to nonfamilial idiopathic dilated cardiomyopathy. J. Cardiol. 2009; 54(1): 66-70.Li L., Pan Y., Dai L., Liu B., Zhang D. Association of genetic polymorphisms on vascular endothelial growth factor and its receptor genes with susceptibility to coronary heart disease. Med. Sci. Monit. 2016; 22: 31-40.Li L., Pan Y., Dai L., Liu B., Zhang D. Association of genetic polymorphisms on vascular endothelial growth factor and its receptor genes with susceptibility to coronary heart disease. Med. Sci. Monit. 2016; 22: 31-40.Lacchini R., Luizon M.R., Gasparini S. et al. Effect of genetic polymorphisms of vascular endothelial growth factor on left ventricular hypertrophy in patients with systemic hypertension. Am. J. Cardiol. 2014; 113(3): 491-496.Lacchini R., Luizon M.R., Gasparini S. et al. Effect of genetic polymorphisms of vascular endothelial growth factor on left ventricular hypertrophy in patients with systemic hypertension. Am. J. Cardiol. 2014; 113(3): 491-496.Yang M., Fu Z., Zhang Q. et al. Association between the polymorphisms in intercellular adhesion molecule-1 and the risk of coronary atherosclerosis: a case-controlled study. PLoS One 2014; 9(10): e109658. doi: 10.1371/journal.pone.0109658Yang M., Fu Z., Zhang Q. et al. Association between the polymorphisms in intercellular adhesion molecule-1 and the risk of coronary atherosclerosis: a case-controlled study. PLoS One 2014; 9(10): e109658. doi: 10.1371/journal.pone.0109658Vargas-Alarcon G., Vallejo M., Posadas-Romero C. et al. The -974C>A (rs3087459) gene polymorphism in the endothelin gene (EDN1) is associated with risk of developing acute coronary syndrome in Mexican patients. Gene 2014; 542(2): 258-262.Vargas-Alarcon G., Vallejo M., Posadas-Romero C. et al. The -974C>A (rs3087459) gene polymorphism in the endothelin gene (EDN1) is associated with risk of developing acute coronary syndrome in Mexican patients. Gene 2014; 542(2): 258-262.Palacín M., Rodriguez-Pascual F., Reguero J.R. et al. Lack of association between endothelin-1 gene variants and myocardial infarction. J. Atheroscler. Thromb. 2009; 16(4): 388-395.Palacín M., Rodriguez-Pascual F., Reguero J.R. et al. Lack of association between endothelin-1 gene variants and myocardial infarction. J. Atheroscler. Thromb. 2009; 16(4): 388-395.Noss E.H., Nguyen H.N., Chang S.K. et al. Genetic polymorphism directs IL-6 expression in fibroblasts but not selected other cell types. Proc. Natl. Acad. Sci. U S A 2015; 112(48): 14948-14953.Noss E.H., Nguyen H.N., Chang S.K. et al. Genetic polymorphism directs IL-6 expression in fibroblasts but not selected other cell types. Proc. Natl. Acad. Sci. U S A 2015; 112(48): 14948-14953.Fishman D., Faulds G., Jeffery R. et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J. Clin. Invest. 1998; 102(7): 1369-1376.Fishman D., Faulds G., Jeffery R. et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J. Clin. Invest. 1998; 102(7): 1369-1376.Ahn M.H., Park B.L., Lee S.H. et al., A promoter SNP rs4073T>A in the common allele of the interleukin 8 gene is associated with the development of idiopathic pulmonary fibrosis via the IL-8 protein enhancing mode. Respir. Res. 2011; 12(1): 73. doi: 10.1186/1465-9921-12-73.Ahn M.H., Park B.L., Lee S.H. et al., A promoter SNP rs4073T>A in the common allele of the interleukin 8 gene is associated with the development of idiopathic pulmonary fibrosis via the IL-8 protein enhancing mode. Respir. Res. 2011; 12(1): 73. doi: 10.1186/1465-9921-12-73.Ohyauchi M., Imatani A., Yonechi M. et al. The polymorphism interleukin 8 -251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut 2005; 54(3): 330-335.Ohyauchi M., Imatani A., Yonechi M. et al. The polymorphism interleukin 8 -251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut 2005; 54(3): 330-335.Rovin B.H., Lu L., Saxena R. A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression. Biochem. Biophys. Res. Commun. 1999; 259(2): 344-348.Rovin B.H., Lu L., Saxena R. A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression. Biochem. Biophys. Res. Commun. 1999; 259(2): 344-348.Prior S.J., Hagberg J.M., Paton C.M. et al. DNA sequence variation in the promoter region of the VEGF gene impacts VEGF gene expression and maximal oxygen consumption. Am. J. Physiol. Heart Circ. Physiol. 2006; 290(5): H1848-1855.Prior S.J., Hagberg J.M., Paton C.M. et al. DNA sequence variation in the promoter region of the VEGF gene impacts VEGF gene expression and maximal oxygen consumption. Am. J. Physiol. Heart Circ. Physiol. 2006; 290(5): H1848-1855.Chen C.F., Liou S.W., Wu H.H. et al. Regulatory SNPs Alter the Gene Expression of Diabetic Retinopathy Associated Secretary Factors. Int. J. Med. Sci. 2016; 13(9): 717-723Chen C.F., Liou S.W., Wu H.H. et al. Regulatory SNPs Alter the Gene Expression of Diabetic Retinopathy Associated Secretary Factors. Int. J. Med. Sci. 2016; 13(9): 717-723Shahbazi M., Fryer A.A., Pravica V. et al. Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J. Am. Soc. Nephrol. 2002; 13(1): 260-264.Shahbazi M., Fryer A.A., Pravica V. et al. Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J. Am. Soc. Nephrol. 2002; 13(1): 260-264.Koukourakis M.I., Papazoglou D., Giatromanolaki A. et al. VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer 2004; 46(3): 293-298.Koukourakis M.I., Papazoglou D., Giatromanolaki A. et al. VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer 2004; 46(3): 293-298.Chen Y., Dawes P.T., Mattey D.L. Polymorphism in the vascular endothelial growth factor A (VEGFA) gene is associated with serum VEGFA level and disease activity in rheumatoid arthritis: differential effect of cigarette smoking. Cytokine 2012; 58(3): 390-397.Chen Y., Dawes P.T., Mattey D.L. Polymorphism in the vascular endothelial growth factor A (VEGFA) gene is associated with serum VEGFA level and disease activity in rheumatoid arthritis: differential effect of cigarette smoking. Cytokine 2012; 58(3): 390-397.Paré G., Chasman D.I., Kellogg M. et al. Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. PLoS Genet. 2008; 4(7): e1000118. doi: 10.1371/journal.pgen.1000118.Paré G., Chasman D.I., Kellogg M. et al. Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. PLoS Genet. 2008; 4(7): e1000118. doi: 10.1371/journal.pgen.1000118.Zang X., Zhou Y., Huang Z., Zhang C. Endothelin-1 single nucleotide polymorphisms and risk of pulmonary metastatic osteosarcoma. PLoS One 2013; 8(9): e73349. doi: 10.1371/journal.pone.0073349Zang X., Zhou Y., Huang Z., Zhang C. Endothelin-1 single nucleotide polymorphisms and risk of pulmonary metastatic osteosarcoma. PLoS One 2013; 8(9): e73349. doi: 10.1371/journal.pone.0073349Nah S.S., Lee H., Hong Y. et al. Association between endothelin-1 and fibromyalgia syndrome. Mol. Med. Rep. 2017; 16(5): 6234-6239.Nah S.S., Lee H., Hong Y. et al. Association between endothelin-1 and fibromyalgia syndrome. Mol. Med. Rep. 2017; 16(5): 6234-6239.

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