Однонуклеотидные полиморфизмы, ассоциированные с повышенным риском развития синдрома раздраженного кишечника с преобладанием запора: метаанализ

Введение. Сочетание генетической предрасположенности с факторами окружающей среды и психоэмоциональным состоянием пациента играет ключевую роль в развитии синдрома раздраженного кишечника (СРК). Изучение ассоциации полиморфизмов генов с СРК может помочь в понимании доминирующих патофизиологических механизмов. На сегодня по данной теме опубликовано 11 метаанализов, однако среди них нет ни одного, который исчерпывающе обобщил бы данные о распространенности генетических полиморфизмов среди пациентов с СРК с преобладанием запора (СРК-З).

Цель: обобщение опубликованных данных о влиянии полиморфизмов генов на риск развития СРК-З.

Материалы и методы. Поиск литературы проводился в электронных базах PubMed и Scopus. На основе найденных исследований проводился метаанализ в соответствии с международными рекомендациями «Предпочитаемые элементы отчетности для систематических обзоров и метаанализов» (Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA). В анализ включались работы, в которых изучалась ассоциация генетических полиморфизмов у пациентов, страдающих СРК-З.

Результаты. Критериям включения соответствовали 34 исследования. Полученных данных оказалось достаточно для проведения метаанализа по полиморфизмам трех из перечисленных генов: SLC6A4 (10 статей), GNB3 (5 статей), ADRA2A (4 статьи). Не было выявлено статистически значимой ассоциации полиморфизма 5-HTTLPR гена SLC6A4 и полиморфизма C825T (rs5443) гена GNB3 как с СРК, так и с СРК-З. Была выявлена статистически значимая ассоциация полиморфизма 1291C>G гена ADRA2A как с СРК, так и с СРК-З.

Выводы. По данным проведенного нами метаанализа выявлена статистически значимая ассоциация полиморфизма 1291C>G гена ADRA2A как с СРК, так и с СРК-З в смешанной популяции. Ни гомозиготный, ни гетерозиготный варианты полиморфизма 5-HTTLPR гена SLC6A4, а также полиморфизма C825T гена GNB3 не были ассоциированы ни с СРК-З, ни с СРК в целом.

1. Mearin F., Lacy B.E., Chang L., Chey W.D., Lembo A.J., Simren M., et al. Bowel disorders. Gastroenterology. 2016;150(6):1393–407.e5. DOI: 10.1053/j.gastro.2016.02.031

2. Mönnikes H. Quality of life in patients with irritable bowel syndrome. J Clin Gastroenterol. 2011;45 Suppl:S98–101. DOI: 10.1097/MCG.0b013e31821fbf44

3. Mishima Y., Ishihara S. Enteric microbiota-mediated serotonergic signaling in pathogenesis of irritable bowel syndrome. Int J Mol Sci. 2021;22(19):10235. DOI: 10.3390/ijms221910235

4. Ford A.C., Sperber A.D., Corsetti M., Camilleri M. Irritable bowel syndrome. Lancet. 2020;396(10263):1675–88. DOI: 10.1016/S0140-6736(20)31548-8

5. Zhu S., Wang B., Jia Q., Duan L. Candidate single nucleotide polymorphisms of irritable bowel syndrome: A systemic review and meta-analysis. BMC Gastroenterol. 2019;19(1):165. DOI: 10.1186/s12876-019-1084-z

6. Czogalla B., Schmitteckert S., Houghton L.A., Sayuk G.S., Camilleri M., Olivo-Diaz A., et al. A meta-analysis of immunogenetic Case-Control Association Studies in irritable bowel syndrome. Neurogastroenterol Motil. 2015;27(5):717–27. DOI: 10.1111/nmo.12548

7. Bashashati M., Rezaei N., Bashashati H., Shafieyoun A., Daryani N.E., Sharkey K.A., et al. Cytokine gene polymorphisms are associated with irritable bowel syndrome: A systematic review and meta-analysis. Neurogastroenterol Motil. 2012;24(12):1102–e566. DOI: 10.1111/j.13652982.2012.01990.x

8. Jia Z., Wang L., Yu B., Li Q., Dong X. Association between polymorphisms in the serotonin transporter gene-linked polymorphic region and risk for irritable bowel syndrome in China: Evidence based on a meta-analysis. J Int Med Res. 2019;47(7):2810–8. DOI: 10.1177/0300060519859144

9. Zhu Y., Zheng G., Hu Z. Association between SERT insertion/deletion polymorphism and the risk of irritable bowel syndrome: A meta-analysis based on 7039 subjects. Gene. 2018;679:133–7. DOI: 10.1016/j.gene.2018.08.059

10. Zhang Z.F., Duan Z.J., Wang L.X., Yang D., Zhao G., Zhang L. The serotonin transporter gene polymorphism (5-HTTLPR) and irritable bowel syndrome: A meta-analysis of 25 studies. BMC Gastroenterol. 2014;14:23. DOI: 10.1186/1471-230X-14-23

11. Areeshi M.Y., Haque S., Panda A.K., Mandal R.K. A serotonin transporter gene (SLC6A4) polymorphism is associated with reduced risk of irritable bowel syndrome in American and Asian population: A meta-analysis. PLoS One. 2013;8(9):e75567. DOI: 10.1371/journal.pone.0075567

12. Van Kerkhoven L.A., Laheij R.J., Jansen J.B. Meta-analysis: A functional polymorphism in the gene encoding for activity of the serotonin transporter protein is not associated with the irritable bowel syndrome. Aliment Pharmacol Ther. 2007;26(7):979–86. DOI: 10.1111/j.1365-2036.2007.03453.x

13. Bashashati M., Moradi M., Sarosiek I. Interleukin-6 in irritable bowel syndrome: A systematic review and meta-analysis of IL-6 (-G174C) and circulating IL-6 levels. Cytokine. 2017;99:132–8. DOI: 10.1016/j.cyto.2017.08.017

14. Pan Z.G., Xiao C., Su D.X. No association of G-protein beta polypeptide 3 polymorphism with irritable bowel syndrome: Evidence from a meta-analysis. World J Gastroenterol. 2014;20(20):6345–52. DOI: 10.3748/wjg.v20. i20.6345

15. Qin S.Y., Jiang H.X., Lu D.H., Zhou Y. Association of interleukin-10 polymorphisms with risk of irritable bowel syndrome: A meta-analysis. World J Gastroenterol. 2013;19(48):9472–80. DOI: 10.3748/wjg.v19.i48.9472

16. Borenstein M., Hedges L.E., Higgins J.P.T., Rothstein H.R. Comprehensive meta-analysis Version 4. Biostat, Inc.; Atlanta, USA: 2022.

17. Borenstein M., Hedges L.E., Higgins J.P.T., Rothstein H.R. Introduction to Meta-Analysis. 2nd ed. Wiley; Hoboken, NJ, USA: 2021.

18. Kim H.J., Camilleri M., Carlson P.J., Cremonini F., Ferber I., Stephens D., et al. Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders. Gut. 2004;53(6):829–37. DOI: 10.1136/gut.2003.030882

19. van der Veek P.P., van den Berg M., de Kroon Y.E., Verspaget H.W., Masclee A.A. Role of tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in irritable bowel syndrome. Am J Gastroenterol. 2005;100(11):2510–6. DOI: 10.1111/j.1572-0241.2005.00257.x

20. Andresen V., Camilleri M., Kim H.J., Stephens D.A., Carlson P.J., Talley N.J., et al. Is there an association between GNbeta3-C825T genotype and lower functional gastrointestinal disorders? Gastroenterology. 2006;130(7):1985–94. DOI: 10.1053/j.gastro.2006.03.017

21. Park J.M., Choi M.G., Park J.A., Oh J.H., Cho Y.K., Lee I.S., et al. Serotonin transporter gene polymorphism and irritable bowel syndrome. Neurogastroenterol Motil. 2006;18(11):995–1000. DOI: 10.1111/j.1365-2982.2006.00829.x

22. Li Y., Nie Y., Xie J., Tang W., Liang P., Sha W., et al. The association of serotonin transporter genetic polymorphisms and irritable bowel syndrome and its influence on tegaserod treatment in Chinese patients. Dig Dis Sci. 2007;52(11):2942–9. DOI: 10.1007/s10620-006-9679-y

23. Saito Y.A., Locke G.R. 3rd., Zimmerman J.M., Holtmann G., Slusser J.P., de Andrade M., et al. A genetic association study of 5-HTT LPR and GNbeta3 C825T polymorphisms with irritable bowel syndrome. Neurogastroenterol Motil. 2007;19(6):465–70. DOI: 10.1111/j.1365-2982.2007.00905.x

24. Camilleri M., Busciglio I., Carlson P., McKinzie S., Burton D., Baxter K., et al. Candidate genes and sensory functions in health and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2008; 295(2):G219–25. DOI: 10.1152/ajpgi.90202.2008

25. Truedsson M., Carlson J., Simrén M., Ohlsson B. Polymorphism in the oxytocin promoter region in patients with lactase non-persistence is not related to symptoms. BMC Gastroenterol. 2009;9:90. DOI: 10.1186/1471-230X-9-90

26. Sikander A., Rana S.V., Sinha S.K., Prasad K.K., Arora S.K., Sharma S.K., et al. Serotonin transporter promoter variant: Analysis in Indian IBS patients and control population. J Clin Gastroenterol. 2009;43(10):957–61. DOI: 10.1097/MCG.0b013e3181b37e8c

27. Niesler B., Kapeller J., Fell C., Atkinson W., Möller D., Fischer C., et al. 5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene and irritable bowel syndrome: Effect of bowel habit and sex. Eur J Gastroenterol Hepatol. 2010;22(7):856–61. DOI: 10.1097/MEG.0b013e32832e9d6b

28. Markoutsaki T., Karantanos T., Gazouli M., Anagnou N.P., Ladas S.D., Karamanolis D.G. Serotonin transporter and G protein beta 3 subunit gene polymorphisms in Greeks with irritable bowel syndrome. Dig Dis Sci. 2011;56(11):3276–80. DOI: 10.1007/s10620-011-1726-7

29. Sikander A., Rana S.V., Sharma S.K., Sinha S.K., Arora S.K., Prasad K.K., et al. Association of alpha 2A adrenergic receptor gene (ADRAlpha2A) polymorphism with irritable bowel syndrome, microscopic and ulcerative colitis. Clin Chim Acta. 2010;411(1–2):59–63. DOI: 10.1016/j.cca.2009.10.003

30. Lee H.J., Lee S.Y., Choi J.E., Kim J.H., Sung I.K., Park H.S., et al. G protein beta3 subunit, interleukin-10, and tumor necrosis factor-alpha gene polymorphisms in Koreans with irritable bowel syndrome. Neurogastroenterol Motil. 2010;22(7):758–63. DOI: 10.1111/j.13652982.2010.01496.x

31. Camilleri M., Vazquez-Roque M.I., Carlson P., Burton D., Wong B.S., Zinsmeister A.R. Association of bile acid receptor TGR5 variation and transit in health and lower functional gastrointestinal disorders. Neurogastroenterol Motil. 2011;23(11):995–9, e458. DOI: 10.1111/j.13652982.2011.01772.x

32. Jun S., Kohen R., Cain K.C., Jarrett M.E., Heitkemper M.M. Associations of tryptophan hydroxylase gene polymorphisms with irritable bowel syndrome. Neurogastroenterol Motil. 2011;23(3):233–9, e116. DOI: 10.1111/j.1365-2982.2010.01623.x

33. Park J.M., Choi M.G., Cho Y.K., Lee I.S., Kim S.W., Choi K.Y., et al. Cannabinoid receptor 1 gene polymorphism and irritable bowel syndrome in the Korean population: A hypothesis-generating study. J Clin Gastroenterol. 2011;45(1):45–9. DOI: 10.1097/MCG.0b013e3181dd1573

34. Zucchelli M., Camilleri M., Andreasson A.N., Bresso F., Dlugosz A., Halfvarson J., et al. Association of TNFSF15 polymorphism with irritable bowel syndrome. Gut. 2011;60(12):1671–7. DOI: 10.1136/gut.2011.241877

35. Kumar S., Ranjan P., Mittal B., Singh R., Ghoshal U.C. Lactase persistence/non-persistence genetic variants in irritable bowel syndrome in an endemic area for lactose malabsorption. J Gastroenterol Hepatol. 2012;27(12):1825–30. DOI: 10.1111/j.1440-1746.2012.07259.x

36. Kumar S., Ranjan P., Mittal B., Ghoshal U.C. Serotonin transporter gene (SLC6A4) polymorphism in patients with irritable bowel syndrome and healthy controls. J Gastrointestin Liver Dis. 2012;21(1):31–8.

37. Sato N., Suzuki N., Sasaki A., Aizawa E., Obayashi T., Kanazawa M., et al. Corticotropin-releasing hormone receptor 1 gene variants in irritable bowel syndrome. PLoS One. 2012;7(9):e42450. DOI: 10.1371/journal.pone.0042450

38. Song Y.A., Park S.Y., Park Y.L., Chung C.Y., Lee G.H., Cho D.H., et al. Association between single nucleotide polymorphisms of the transient receptor potential vanilloid 1 (TRPV-1) gene and patients with irritable bowel syndrome in Korean populations. Acta Gastroenterol Belg. 2012;75(2):222–7.

39. Swan C., Duroudier N.P., Campbell E., Zaitoun A., Hastings M., Dukes G.E., et al. Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): Association with TNFSF15 and TNFα. Gut. 2013;62(7):985–94. DOI: 10.1136/gutjnl-2011-301213

40. Uğur Kantar F., Simşek İ., Ercal D., Ülgenalp A., Bora E. Alpha-2-adrenergic receptor gene polymorphism in Turkish population with irritable bowel syndrome. Turk J Gastroenterol. 2013;24(6):483–8.

41. Schmulson M., Pulido-London D., Rodríguez Ó., Morales-Rochlin N., Martínez-García R., Gutiérrez-Ruiz M.C., et al. IL-10 and TNF-alpha polymorphisms in subjects with irritable bowel syndrome in Mexico. Rev Esp Enferm Dig. 2013;105(7):392–9. DOI: 10.4321/s1130-01082013000700004

42. Camilleri M., Kolar G.J., Vazquez-Roque M.I., Carlson P., Burton D.D., Zinsmeister A.R. Cannabinoid receptor 1 gene and irritable bowel syndrome: Phenotype and quantitative traits. Am J Physiol Gastrointest Liver Physiol. 2013;304(5):G553–60. DOI: 10.1152/ajpgi.00376.2012

43. Colucci R., Gambaccini D., Ghisu N., Rossi G., Costa F., Tuccori M., De Bortoli N., Fornai M., Antonioli L., Ricchiuti A., Mumolo M.G., Marchi S., Blandizzi C., Bellini M. Influence of the serotonin transporter 5HTTLPR polymorphism on symptom severity in irritable bowel syndrome. PLoS One. 2013;8(2):e54831. DOI: 10.1371/journal.pone.0054831.

44. Farjadian S., Fakhraei B., Moeini M., Nasiri M., Fattahi M.R. Serotonin transporter gene polymorphisms in Southwestern Iranian patients with irritable bowel syndrome. Arab J Gastroenterol. 2013;14(2):59–62. DOI: 10.1016/j.ajg.2013.03.001

45. Grasberger H., Chang L., Shih W., Presson A.P., Sayuk G.S., Newberry R.D., et al. Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes. Am J Gastroenterol. 2013;108(11):1766–74. DOI: 10.1038/ajg.2013.304

46. Wouters M.M., Lambrechts D., Knapp M., Cleynen I., Whorwell P., Agréus L., et al. Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome. Gut. 2014;63(7):1103–11. DOI: 10.1136/gutjnl-2013-304570

47. Wang Y., Wu Z., Qiao H., Zhang Y. A genetic association study of single nucleotide polymorphisms in GNβ3 and COMT in elderly patients with irritable bowel syndrome. Med Sci Monit. 2014;20:1246–54. DOI: 10.12659/MSM.890315

48. Jiang Y., Nie Y., Li Y., Zhang L. Association of cannabinoid type 1 receptor and fatty acid amide hydrolase genetic polymorphisms in Chinese patients with irritable bowel syndrome. J Gastroenterol Hepatol. 2014;29(6):1186–91. DOI: 10.1111/jgh.12513

49. Romero P., Schmitteckert S., Wouters M.M., Houghton L.A., Czogalla B., Sayuk G.S., et al. No association between the common calcium-sensing receptor polymorphism rs1801725 and irritable bowel syndrome. BMC Med Genet. 2015;16:110. DOI: 10.1186/s12881-015-0256-0

50. Komuro H., Sato N., Sasaki A., Suzuki N., Kano M., Tanaka Y., et al. Corticotropin-releasing hormone receptor 2 gene variants in irritable bowel syndrome. PLoS One. 2016;11(1):e0147817. DOI: 10.1371/journal.pone.0147817

51. Almazar A.E., Chang J.Y., Larson J.J., Atkinson E.J., Locke G.R., Talley N.J., et al. Comparison of lactase variant MCM6-13910 C > T testing and self-report of dairy sensitivity in patients with irritable bowel syndrome.