pmjТихоокеанский медицинский журналPacific Medical Journal1609-1175TGMU10.34215/1609-1175-2020-4-44-48pmj-2122Research ArticleОБЗОРЫREVIEWSРоль полиморфизма генов интерлейкина-1β и антагониста рецептора интерлейкина-1, инфекции Helicobacter pylori и состояния слизистой оболочки желудка в развитии и прогрессировании гастроэзофагеальной рефлюксной болезниThe role of interleukin 1β and interleukin 1 receptor antagonist polymorphism genes, Helicobacter pylori infection and the state of the gastric mucosa in the development and progression of gastroesophageal reflux diseasehttps://orcid.org/0000-0002-4405-2975ЖилинаА. А.ZhilinaA. A.

канд. мед. наук, доцент кафедры терапии ФПК и ППС,

672000, г. Чита, ул. Балябина, 14/411

MD, PhD, associate professor, 

14/411 Balabina St., Chita, 672000

albina1228@yandex.ruhttps://orcid.org/0000-0001-9498-9216ЛареваН. В.LarevaN. V.

д-р мед. наук, профессор, заведующая кафедрой терапии ФПК и ППС,

672000, г. Чита, ул. Балябина, 14/411

MD, PhD, professor, 

14/411 Balabina St., Chita, 672000

larevanv@mail.ruhttps://orcid.org/0000-0002-8282-3056ЛузинаЕ. В.LuzinaE. V.

доцент кафедры терапии ФПК и ППС ФГБОУ канд. мед. наук, доцент кафедры терапии ФПК и ППС,

672000, г. Чита, ул. Балябина, 14/411

MD, PhD, associate professor, 

14/411 Balabina St., Chita, 672000

el.luz@list.ruЧитинская государственная медицинская академияРоссияChita State Medical AcademyRussian Federation202028122020044448Copyright © Жилина А.А., Ларева Н.В., Лузина Е.В., 20202020Жилина А.А., Ларева Н.В., Лузина Е.В.Zhilina A.A., Lareva N.V., Luzina E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.tmj-vgmu.ru/jour/article/view/2122

Механизмы развития гастроэзофагеальной рефлюксной болезни (ГЭРБ) и ее осложнений рассматриваются в том числе на тканевом и клеточном уровнях, поэтому изучение полиморфизма генов интерлейкинов (ИЛ) при данной патологии становится актуальным. Генотипы ИЛ-1β-511Т/Т, ИЛ-1β31С/С и ИЛ-1RN2/2 (антагониста рецептора ИЛ-1) ассоциируются с высоким риском осложненного течения ГЭРБ. При исследовании полиморфизма генов провоспалительных цитокинов у пациентов с гастроэзофагеальным рефлюксом и изменениями слизистой оболочки желудка, установлено, что генотип ИЛ-1β-511Т/Т ассоциирован с более высоким локальным уровнем ИЛ-1β. При этом уровень ИЛ-1β был ниже у больных с эрозивным эзофагитом. Установлено, что генотип ИЛ-1RN2/2 и гаплотип ИЛ-1RN*2 / ИЛ-1В-31*Т связаны с повышенным риском рака желудка у Helicobacter pylori-позитивных больных. У пациентов с ГЭРБ генотип ИЛ-1β-511Т/Т и гаплотип ИЛ-1β-511Т/Т / ИЛ-1RN1/1 ассоциированы с низким риском рака пищевода. Таким образом, аллель ИЛ-1RN*2 и генотип ИЛ-1RN2/2 могут считаться независимыми предикторами прогрессирования ГЭРБ. Работы в этом направлении должны быть продолжены не только с учетом изменений слизистой оболочки желудка, наличия хеликобактериоза, но и характера пищеводного рефлюктата.

The mechanisms of the gastroesophageal reflux disease (GERD) development and its complications are analyzed on the tissue and cell levels. That’s why studying polymorphism of interleukin (IL) genes is important. Genotypes IL1β-511Т/Т, IL1β31С/С and IL1RN2/2 (receptor antagonist IL1) associate with high risk of complicated course of GERD disease. Researching genes polymorphism of the pro-inflammatory cytokines of the patients having gastroesophageal reflux disease and changes in gastric mucosa it was determined that genotype IL1β-511Т/Т is associated with the deeper local level of IL1β. Meanwhile the patients having erosive esophagitis had lover level of IL1β. It was determined that genotype IL1RN2/2 and haplotype IL1RN*2 /IL1В-31*Т are connected with the high risk of esophagus cancer of patients having Helicobacter pylori. Genotype IL1β-511Т/Т and haplotype IL1β-511Т/Т /IL1RN1/1 of the patients having GERD are associated with the low risk of the esophagus cancer. So, the allele IL1RN*2 and genotype IL1RN2/2 can combine by independent predictors of GERD progression. The study of this field should be continued taking into account not only changes in gastric mucosa, presence of helicobacteriosis, but also the nature of gastroesophageal reflux.

гастроэзофагеальный рефлюксполиморфизм геновинтерлейкиныHelicobacter pyloriрак пищеводаgastroesophageal refluxgene polymorphisminterleukinHelicobacter pyloriesophagus cancerReferencesЛямина С.В., Маев И.В., Калиш С.В., Андреев Д.Н., Кладовикова О.В., Малышев И.Ю. Особенности функциональной активности макрофагального иммунитета при гастроэзофагеальной рефлюксной болезни в зависимости от типа рефлюктата: in vitro модель. Терапевтический архив. 2018;2:19–23.Lyamina SV, Maev IV., Kalish SV, Andreev DN, Kladovikova OV, Malyshev IYu. Features of the functional activity of macrophage link of immunity with gastroesophageal reflux disease depending on the type of reluctate: in vitro model. Тerapevticheskii arkhiv. 2018;2:19–23 (In Russ).Zheng L, Yin J, Wang L, Wang X, Shi Y, Shao A, Tang W, et al. Interleukin 1B rs16944 G>A polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population. Clini Biochem. 2013;46(15):1469–73.Zheng L, Yin J, Wang L, Wang X, Shi Y, Shao A, Tang W, et al. Interleukin 1B rs16944 G>A polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population. Clini Biochem. 2013;46(15):1469–73.Isomoto H, Wang AP, Nishi Y, Matsumoto A, Shikuwa S, Mizuta Y, et al. Interleukin 8 and 1 beta and RANTES levels in esophageal mucosa predict recurrence of endoscopynegative gastroesophageal reflux disease. Hepato-gastroenterol. 2008;55(82–83):482–5.Isomoto H, Wang AP, Nishi Y, Matsumoto A, Shikuwa S, Mizuta Y, et al. Interleukin 8 and 1 beta and RANTES levels in esophageal mucosa predict recurrence of endoscopynegative gastroesophageal reflux disease. Hepato-gastroenterol. 2008;55(82–83):482–5.Rieder F, Cheng L, Harnett KM, Chak A, Cooper GS, Isenberg G, et al. Gastroesophageal reflux disease-associated esophagitis induces endogenous cytokine production leading to motor abnormalities. Gastroenterol. 2006;132(1):154–65.Rieder F, Cheng L, Harnett KM, Chak A, Cooper GS, Isenberg G, et al. Gastroesophageal reflux disease-associated esophagitis induces endogenous cytokine production leading to motor abnormalities. Gastroenterol. 2006;132(1):154–65.Koivurova OP, Karhukorpi JMJ, Joensuu ET, Koistinen PO, Valtonen JM, Karttunen TJ, et al. IL-1 RN 2/2 genotype and simultaneous carriage of genotypes IL-1 RN 2/2 and IL-1 beta-511 T/T associated with oesophagitis in Helicobacter pylori-negative patients. Scand J Gastroenterol. 2003;38(12):1217–22.Koivurova OP, Karhukorpi JMJ, Joensuu ET, Koistinen PO, Valtonen JM, Karttunen TJ, et al. IL-1 RN 2/2 genotype and simultaneous carriage of genotypes IL-1 RN 2/2 and IL-1 beta-511 T/T associated with oesophagitis in Helicobacter pylori-negative patients. Scand J Gastroenterol. 2003;38(12):1217–22.Ando T, El-Omar EM, Goto Y, Nobata K, Watanabe O, Maeda O, et al. Interleukin 1B proinflammatory genotypes protect against gastro-oesophageal reflux disease through induction of corpus atrophy. Gut. 2006;55(2):158–64.Ando T, El-Omar EM, Goto Y, Nobata K, Watanabe O, Maeda O, et al. Interleukin 1B proinflammatory genotypes protect against gastro-oesophageal reflux disease through induction of corpus atrophy. Gut. 2006;55(2):158–64.Akçil G, Doğan İ, Cengiz M, Engin ED, Doğan M, Ünal S, et al. The role of interleukin-1 gene polymorphisms and Helicobacter pylori in gastroesophageal reflux disease. Turk J Gastroenterol. 2014;25(1):81–5.Akçil G, Doğan İ, Cengiz M, Engin ED, Doğan M, Ünal S, et al. The role of interleukin-1 gene polymorphisms and Helicobacter pylori in gastroesophageal reflux disease. Turk J Gastroenterol. 2014;25(1):81–5.Chourasia D, Achyut BR, Tripathi S, Mittal B, Mittal RD, Ghoshal UC. Genotypic and functional roles of IL-1B and IL-1RN on the risk of gastroesophageal reflux disease: The presence of IL-1B511*T/IL-1RN*1 (T1) haplotype may protect against the disease. Am J Gastroenterol. 2009;104(11):2704–13.Chourasia D, Achyut BR, Tripathi S, Mittal B, Mittal RD, Ghoshal UC. Genotypic and functional roles of IL-1B and IL-1RN on the risk of gastroesophageal reflux disease: The presence of IL-1B511*T/IL-1RN*1 (T1) haplotype may protect against the disease. Am J Gastroenterol. 2009;104(11):2704–13.Queiroz DM, Guerra JB, Rocha GA, Rocha AM, Santos A, De Oliveira AG, et al. IL1B and IL1RN polymorphic genes and Helicobacter pylori cagA strains decrease the risk of reflux esophagitis. Gastroenterol. 2004;127(1):73–9.Queiroz DM, Guerra JB, Rocha GA, Rocha AM, Santos A, De Oliveira AG, et al. IL1B and IL1RN polymorphic genes and Helicobacter pylori cagA strains decrease the risk of reflux esophagitis. Gastroenterol. 2004;127(1):73–9.Kim JJ, Kim J, Hwang S, Kim JY, Kim JY, Choi YJ, et al. Relationship of interleukin-1β levels and gastroesophageal reflux disease in Korea. J Gastroenterol Hepatol. 2012;28(1):90–8.Kim JJ, Kim J, Hwang S, Kim JY, Kim JY, Choi YJ, et al. Relationship of interleukin-1β levels and gastroesophageal reflux disease in Korea. J Gastroenterol Hepatol. 2012;28(1):90–8.Zabaleta J, Camargo MC, Piazuelo MB, Fontham E, Schneider BG, Sicinschi LA, et al. Association of interleukin-1 beta gene polymorphisms with precancerous gastric lesions in African Americans and Caucasians. Am J Gastroenterol. 2006;101(1):163–71.Zabaleta J, Camargo MC, Piazuelo MB, Fontham E, Schneider BG, Sicinschi LA, et al. Association of interleukin-1 beta gene polymorphisms with precancerous gastric lesions in African Americans and Caucasians. Am J Gastroenterol. 2006;101(1):163–71.Kupcinskas L, Wex T, Kupcinskas J, Leja M, Ivanauskas A, Jonaitis LV, et al. Interleukin-1B and interleukin-1 receptor antagonist gene polymorphisms are not associated with premalignant gastric conditions: a combined haplotype analysis. Eur J Gastroenterol Hepatol. 2010;22(10):1189–95.Kupcinskas L, Wex T, Kupcinskas J, Leja M, Ivanauskas A, Jonaitis LV, et al. Interleukin-1B and interleukin-1 receptor antagonist gene polymorphisms are not associated with premalignant gastric conditions: a combined haplotype analysis. Eur J Gastroenterol Hepatol. 2010;22(10):1189–95.Rocha GA, Guerra JB, Rocha AMC, Saraiva IEB, da Silva DA, de Oliveira CA. IL1RN polymorphic gene and cagA-positive status independently increase the risk of noncardia gastric carcinoma. Int J Cancer. 2005;115(5):678–83.Rocha GA, Guerra JB, Rocha AMC, Saraiva IEB, da Silva DA, de Oliveira CA. IL1RN polymorphic gene and cagA-positive status independently increase the risk of noncardia gastric carcinoma. Int J Cancer. 2005;115(5):678–83.Crusius JBA, Canzian F, Capella G, Pena AS, Pera G, Sala N, et al. Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST). Ann Oncol. 2008;19(11):1894–902.Crusius JBA, Canzian F, Capella G, Pena AS, Pera G, Sala N, et al. Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST). Ann Oncol. 2008;19(11):1894–902.Palli D, Saieva C, Luzzi I, Masala G, Topa S, Sera F, et al. Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk Italian population. Am J Gastroenterol. 2005;100(9):1941–8.Palli D, Saieva C, Luzzi I, Masala G, Topa S, Sera F, et al. Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk Italian population. Am J Gastroenterol. 2005;100(9):1941–8.Perri F, Piepoli A, Bonvicini C, Gentile A, Quitadamo M, Di Candia M, et al. Cytokine gene polymorphisms in gastric cancer patients from two Italian areas at high and low cancer prevalence. Cytokine. 2005;30(5):293–302.Perri F, Piepoli A, Bonvicini C, Gentile A, Quitadamo M, Di Candia M, et al. Cytokine gene polymorphisms in gastric cancer patients from two Italian areas at high and low cancer prevalence. Cytokine. 2005;30(5):293–302.Yamada S, Matsuhisa T, Makonkawkeyoon L, Chaidatch S, Kato S, Matsukura N. Helicobacter pylori infection in combination with the serum pepsinogen I/II ratio and interleukin-1 beta-511 polymorphisms are independent risk factors for gastric cancer in Thais. J Gastroenterol. 2006;41(12):1169–77.Yamada S, Matsuhisa T, Makonkawkeyoon L, Chaidatch S, Kato S, Matsukura N. Helicobacter pylori infection in combination with the serum pepsinogen I/II ratio and interleukin-1 beta-511 polymorphisms are independent risk factors for gastric cancer in Thais. J Gastroenterol. 2006;41(12):1169–77.Garza-Gonzalez E, Bosques-Padilla FJ, El-Omar E, Hold G, Tijerina-Menchaca R, Maldonado-Garza HJ, Perez-Perez GI. Role of the polymorphic IL-1B, IL-1RN and TNF-A genes in distal gastric cancer in Mexico. Int J Cancer. 2005;114(2):237–41.Garza-Gonzalez E, Bosques-Padilla FJ, El-Omar E, Hold G, Tijerina-Menchaca R, Maldonado-Garza HJ, Perez-Perez GI. Role of the polymorphic IL-1B, IL-1RN and TNF-A genes in distal gastric cancer in Mexico. Int J Cancer. 2005;114(2):237–41.Ito H, Kaneko K, Makino R, Konishi K, Kurahashi T, Yamamoto T, et al. Interleukin-1beta gene in esophageal, gastric and colorectal carcinomas. Oncol Rep. 2007;18(2):473–81.Ito H, Kaneko K, Makino R, Konishi K, Kurahashi T, Yamamoto T, et al. Interleukin-1beta gene in esophageal, gastric and colorectal carcinomas. Oncol Rep. 2007;18(2):473–81.Persson C, Engstrand L, Nyren O, Hansson LE, Enroth H, Ekstrom AM, Ye WM. Interleukin 1-gene polymorphisms and risk of gastric cancer in Sweden. Scand J Gastroenterol. 2009;44(3):339–45.Persson C, Engstrand L, Nyren O, Hansson LE, Enroth H, Ekstrom AM, Ye WM. Interleukin 1-gene polymorphisms and risk of gastric cancer in Sweden. Scand J Gastroenterol. 2009;44(3):339–45.Xue HP, Lin B, Ni PH, Xu H, Huang G. Interleukin-1B and interleukin-1 RN polymorphisms and gastric carcinoma risk: A meta-analysis. J Gastroenterol Hepatol. 2010;25(10):1604–17.Xue HP, Lin B, Ni PH, Xu H, Huang G. Interleukin-1B and interleukin-1 RN polymorphisms and gastric carcinoma risk: A meta-analysis. J Gastroenterol Hepatol. 2010;25(10):1604–17.Kulmambetova GN, Imanbekova MK, Logvinenko AA, Sukashev AT, Filipenko ML, Ramanculov EM. Association of cytokine gene polymorphisms with gastritis in a Kazakh population. Asian Pac J Cancer Prev. 2014;15(18):7763–8.Kulmambetova GN, Imanbekova MK, Logvinenko AA, Sukashev AT, Filipenko ML, Ramanculov EM. Association of cytokine gene polymorphisms with gastritis in a Kazakh population. Asian Pac J Cancer Prev. 2014;15(18):7763–8.Cheng H, Chang C, Wang H, Wang W. Interleukin-1β and -10 polymorphisms influence erosive reflux esophagitis and gastritis in Taiwanese patients. J Gastroenterol Hepatol. 2010;8:1443–51.Cheng H, Chang C, Wang H, Wang W. Interleukin-1β and -10 polymorphisms influence erosive reflux esophagitis and gastritis in Taiwanese patients. J Gastroenterol Hepatol. 2010;8:1443–51.Izakovicova HL, Borilova LP, Hrdlickova B, Marek F, Dolina J, Rihak V, Kala Z. Haplotypes of the IL-1 gene cluster are associated with gastroesophageal reflux disease and Barrett’s esophagus. Hum Immunol. 2013;74(9):1161–9.Izakovicova HL, Borilova LP, Hrdlickova B, Marek F, Dolina J, Rihak V, Kala Z. Haplotypes of the IL-1 gene cluster are associated with gastroesophageal reflux disease and Barrett’s esophagus. Hum Immunol. 2013;74(9):1161–9.Xue MM, Li J, Li W, Wang DX. Association of interleukin-1B gene polymorphisms at site 511 with gastroesophageal reflux disease: A meta-analysis. Esophagus. 2016;13(1):74–9.Xue MM, Li J, Li W, Wang DX. Association of interleukin-1B gene polymorphisms at site 511 with gastroesophageal reflux disease: A meta-analysis. Esophagus. 2016;13(1):74–9.Kavanagh ME, Conroy MJ, Clarke NE, Gilmartin NT, O’Sullivan KE, Feighery R, et al. Impact of the inflammatory microenvironment on T-cell phenotype in the progression from refluxoesophagitis to Barrett oesophagus and oesophageal adenocarcinoma. Cancer Lett. 2016;370(1):117–24.Kavanagh ME, Conroy MJ, Clarke NE, Gilmartin NT, O’Sullivan KE, Feighery R, et al. Impact of the inflammatory microenvironment on T-cell phenotype in the progression from refluxoesophagitis to Barrett oesophagus and oesophageal adenocarcinoma. Cancer Lett. 2016;370(1):117–24.Deans DAC, Wigmore SJ, Gilmour H, Paterson-Brown S, Ross JA, Fearon KCH. Elevated tumour interleukin-1 beta is associated with systemic inflammation: A marker of reduced survival in gastro-oesophageal cancer. Br J Cancer. 2006;95 (11):1568–75.Deans DAC, Wigmore SJ, Gilmour H, Paterson-Brown S, Ross JA, Fearon KCH. Elevated tumour interleukin-1 beta is associated with systemic inflammation: A marker of reduced survival in gastro-oesophageal cancer. Br J Cancer. 2006;95 (11):1568–75.Muramatsu A, Azuma T, Okuda T, Satomi S, Ohtani M, Lee S, et al. Association between interleukin-1 beta-511C/T polymorphism and reflux esophagitis in Japan. J Gastroenterol. 2005;40(9):873–7.Muramatsu A, Azuma T, Okuda T, Satomi S, Ohtani M, Lee S, et al. Association between interleukin-1 beta-511C/T polymorphism and reflux esophagitis in Japan. J Gastroenterol. 2005;40(9):873–7.Upadhyay R, Jain M, Kumar S, Ghosh UC, Mittal B. Potential influence of interleukin-1 haplotype IL-1 beta-511*T-IL1RN*1 in conferring low risk to middle third location of esophageal cancer: A case-control study. Hum Immunol. 2008; 69(3):179–86.Upadhyay R, Jain M, Kumar S, Ghosh UC, Mittal B. Potential influence of interleukin-1 haplotype IL-1 beta-511*T-IL1RN*1 in conferring low risk to middle third location of esophageal cancer: A case-control study. Hum Immunol. 2008; 69(3):179–86.Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut. 2009;58(2):295–309.Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut. 2009;58(2):295–309.Кайбышева В.О., Трухманов А.С., Сторонова О.А. Морфофункциональные изменения в пищеводе при ГЭРБ в зависимости от характера рефлюктата. Клинические перспективы гастроэнтерологии, гепатологии. 2014;5:28–36.Kaybysheva VO, Trukhmanov AS, Storonova OA. Morphofunctional changes in the esophagus with GERD, depending on the nature of refluxate. Clinical Perspectives of Gastroenterology, Hepatology. 2014;5:28–36 (In Russ).

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