Skip to main content

Advertisement

SpringerLink
Log in

Genetic polymorphism of pri-microRNA 325, targeting SLC6A4 3′-UTR, is closely associated with the risk of functional dyspepsia in Japan

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

The role of genetics in the susceptibility to functional dyspepsia (FD) remains unclear. We attempted to clarify the association between FD and polymorphisms in SLC6A4. In addition, rs5981521 (C>T) in the pri-microRNA 325 (pri-miR-325) coding region was also investigated.

Methods

The study was performed in 395 subjects (172 with no upper abdominal symptoms and 223 with FD, including medication-resistant FD). We employed a polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method to detect gene polymorphisms.

Results

Neither SLC6A4 −185 A>C nor *463 G>T was associated with susceptibility to FD. The number of rs5981521 T alleles was significantly correlated with an increased risk for FD (odds ratio [OR] 1.45, 95 % confidence interval [CI] 1.05–1.98; p = 0.022) and the TT homozygote was more closely associated with the risk for FD (OR 3.01, 95 % CI 1.41–6.42; p = 0.0043). The TT homozygote also had significantly increased risks for both the epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS) subtypes of FD (OR 3.04, 95 % CI 1.25–7.42; p = 0.014 and OR 3.05, 95 % CI 1.14–8.13; p = 0.026, respectively). In addition, Helicobacter pylori-negative TT homozygotes had a greater risk for FD (OR 8.37, 95 % CI 1.78–39.5; p = 0.0072). In subjects with the SLC6A4 5′-untranslated region (UTR) wild homozygote, the number of rs5981521 T alleles was significantly correlated to an increased risk for FD (OR 1.45, 95 % CI 1.03–2.04, p = 0.033). Of note, in subjects who were SLC6A4 3′-UTR mutant carriers, the number of rs5981521 T alleles was also significantly correlated with an increased risk for FD (OR 2.07, 95 % CI 1.08–3.98; p = 0.029).

Conclusions

Our results suggest that the genetic polymorphism pri-miR-325 is associated with FD and interacts with SLC6A4 polymorphisms in increasing susceptibility to FD in Japanese.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Talley NJ, Stanghellini V, Heading RC, Koch KL, Malagelada JR, Tytgat GN. Functional gastro duodenal disorders. Gut. 1999;45(suppl II):II37–42.

    Article  PubMed  Google Scholar 

  2. Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of functional dyspepsia. Gastroenterology. 2004;127:1239–55.

    Article  PubMed  Google Scholar 

  3. Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology. 1998;115:1346–52.

    Article  PubMed  CAS  Google Scholar 

  4. Lunding JA, Tefera S, Gilja OH, Hausken T, Bayati A, Rydholm H, et al. Rapid initial gastric emptying and hypersensitivity to gastric filling in functional dyspepsia: effects of duodenal lipids. Scand J Gastroenterol. 2006;41:1028–36.

    Article  PubMed  Google Scholar 

  5. Chen TS, Lee YC, Chang FY, Wu HC, Lee SD. Psychosocial distress is associated with abnormal gastric myoelectrical activity in patients with functional dyspepsia. Scand J Gastroenterol. 2006;41:791–6.

    Article  PubMed  Google Scholar 

  6. Locke GR, Weaver AL, Melton LJ, Talley NJ. Psychosocial factors are linked to functional gastrointestinal disorders: a population based nested case–control study. Am J Gastroenterol. 2004;99:350–7.

    Article  PubMed  Google Scholar 

  7. Mahadeva S, Goh KL. Epidemiology of functional dyspepsia: a global perspective. World J Gastroenterol. 2006;12:2661–6.

    PubMed  Google Scholar 

  8. Locke GR 3rd, Zinsmeister AR, Talley NJ, Fett SL, Melton LJ 3rd. Familial association in adults with functional gastrointestinal disorders. Mayo Clin Proc. 2000;75:907–12.

    Article  PubMed  Google Scholar 

  9. Holtmann G, Siffert W, Haag S, Mueller N, Langkafel M, Senf W, et al. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology. 2004;126:971–9.

    Article  PubMed  CAS  Google Scholar 

  10. Gebhart GF. Pathobiology of visceral pain: molecular mechanisms and therapeutic implications: IV. Visceral afferent contributions to the pathobiology of visceral pain. Am J Physiol Gastrointest Liver Physiol. 2000;278:G834–8.

    PubMed  CAS  Google Scholar 

  11. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397–414.

    Article  PubMed  CAS  Google Scholar 

  12. Lesch K, Bengel D, Heils A, Sabol S, Greenberg B, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274:1527–31.

    Article  PubMed  CAS  Google Scholar 

  13. Ogilvie A, Battersby S, Bubb V, Fink G, Harmar A, Goodwim G, et al. Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet. 1996;347:731–3.

    Article  PubMed  CAS  Google Scholar 

  14. Ho P, Shih M, Ma K, Huang W, Ho K, Yen C, et al. Availability of the serotonin transporter in patients with alcohol dependence. World J Biol Psychiatry. 2011;12:134–42.

    Article  PubMed  CAS  Google Scholar 

  15. Pata C, Erdal M, Derici E, Yazar A, Kanik A, Ulu O. Serotonin transporter gene polymorphism in irritable bowel syndrome. Am J Gastroenterol. 2002;97:1780–4.

    Article  PubMed  CAS  Google Scholar 

  16. Park J, Choi M, Park J, Oh J, Cho Y, Lee I, et al. Serotonin transporter gene polymorphism and irritable bowel syndrome. Neurogastroenterol Motil. 2006;18:995–1000.

    Article  PubMed  CAS  Google Scholar 

  17. Saito Y, Locke G, Zimmerman J, Holtmann G, Slusser J, De Andrade M, et al. A genetic association study of 5-HTT LPR and GN beta 3 C825T polymorphisms with irritable bowel syndrome. Neurogastroenterol Motil. 2007;19:465–70.

    Article  PubMed  CAS  Google Scholar 

  18. Camilleri C, Carlson P, Camilleri M, Castillo E, Locke GR, Geno D. A study of candidate genotypes associated with dyspepsia in a U.S. community. Am J Gastroenterol. 2006;101:581–92.

    Article  PubMed  CAS  Google Scholar 

  19. van Lelyveld N, Linde J, Schipper M, Samsom M. Candidate genotypes associated with functional dyspepsia. Neurogastroenterol Motil. 2008;20:767–73.

    Article  PubMed  Google Scholar 

  20. Toyoshima F, Oshima T, Nakajima S, Sakurai J, Tanaka J, Tomita T, et al. Serotonin transporter gene polymorphism may be associated with functional dyspepsia in a Japanese population. BMC Med Genet. 2011;12:88.

    Article  PubMed  CAS  Google Scholar 

  21. Su S, Zhao J, Bremner JD, Miller AH, Tang W, Bouzyk M, et al. Serotonin transporter gene, depressive symptoms, and interleukin-6. Circ Cardiovasc Genet. 2009;2:614–20.

    Article  PubMed  CAS  Google Scholar 

  22. Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y, et al. The relationship between Helicobacter pylori infection and promoter polymorphism of the Nrf2 gene in chronic gastritis. Int J Mol Med. 2007;19:143–8.

    PubMed  CAS  Google Scholar 

  23. Shiroeda H, Tahara T, Nakamura M, Shibata T, Nomura T, Yamada H, et al. Association between functional promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene and ulcerative colitis in Japan. Cytokine. 2010;51:173–7.

    Article  PubMed  CAS  Google Scholar 

  24. Aggarwal A, Cutts TF, Abell TL, Cardoso S, Familoni B, Bremer J, et al. Predominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities. Gastroenterology. 1994;106:945–50.

    PubMed  CAS  Google Scholar 

  25. Kim DY, Camilleri M. Serotonin: a mediator of the brain-gut connection. Am J Gastroenterol. 2000;95:2698–709.

    PubMed  CAS  Google Scholar 

  26. Raynor HA, Epstein LH. Effects of sensory stimulation and post-ingestive consequences on satiation. Physiol Behav. 2000;70:465–70.

    Article  PubMed  CAS  Google Scholar 

  27. Martel F. Recent advances on the importance of the serotonin transporter SERT in the rat intestine. Pharmacol Res. 2006;54:73–6.

    Article  PubMed  CAS  Google Scholar 

  28. Coates MD, Johnson AC, Greenwood-Van Meerveld B, Mawe GM. Effects of serotonin transporter inhibition on gastrointestinal motility and colonic sensitivity in the mouse. Neurogastroenterol Motil. 2006;18:464–71.

    Article  PubMed  CAS  Google Scholar 

  29. Camilleri M, Andrews CN, Bharucha AE, Carlson PJ, Ferber I, Stephens D, et al. Alterations in expression of p11 and SERT in mucosal biopsy specimens of patients with irritable bowel syndrome. Gastroenterology. 2007;132:17–25.

    Article  PubMed  CAS  Google Scholar 

  30. Tian XY, Bian ZX, Hu XG, Zhang XJ, Liu L, Zhang H. Electro-acupuncture attenuates stress-induced defecation in rats with chronic visceral hypersensitivity via serotonergic pathway. Brain Res. 2006;1088:101–8.

    Article  PubMed  CAS  Google Scholar 

  31. Faure C, Patey N, Gauthier C, Brooks EM, Mawe GM. Serotonin signaling is altered in irritable bowel syndrome with diarrhea but not in functional dyspepsia in pediatric age patients. Gastroenterology. 2010;139:249–58.

    Article  PubMed  CAS  Google Scholar 

  32. van Lelyveld N, Ter Linde J, Schipper ME, Samsom M. Regional differences in expression of TPH-1, SERT, 5-HT(3) and 5-HT(4) receptors in the human stomach and duodenum. Neurogastroenterol Motil. 2007;19:342–8.

    Article  PubMed  Google Scholar 

  33. Mishra PJ, Bertino JR. MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics. 2009;10:399–416.

    Article  PubMed  CAS  Google Scholar 

  34. Duan R, Pak C, Jin P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124–31.

    Article  PubMed  CAS  Google Scholar 

  35. Linden DR, Foley KF, McQuoid C, Simpson J, Sharkey KA, Mawe GM. Serotonin transporter function and expression are reduced in mice with TNBS-induced colitis. Neurogastroenterol Motil. 2005;17:565–74.

    Article  PubMed  CAS  Google Scholar 

  36. Wheatcroft J, Wakelin D, Smith A, Mahoney CR, Mawe G, Spiller R. Enterochromaffin cell hyperplasia and decreased serotonin transporter in a mouse model of postinfectious bowel dysfunction. Neurogastroenterol Motil. 2005;17:863–70.

    Article  PubMed  CAS  Google Scholar 

  37. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process. First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;52:6735–40.

    PubMed  CAS  Google Scholar 

  38. Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Hirata I, et al. Homozygous TRPV1 315C influences the susceptibility to functional dyspepsia. J Clin Gastroenterol. 2010;44:e1–7.

    Article  PubMed  CAS  Google Scholar 

  39. Bielefeldt K, Davis BM. Differential effects of ASIC3 and TRPV1 deletion on gastroesophageal sensation in mice. Am J Physiol Gastrointest Liver Physiol. 2008;294:G130–8.

    Article  PubMed  CAS  Google Scholar 

  40. Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y, et al. Genetic polymorphisms of molecules associated with inflammation and immune response in Japanese subjects with functional dyspepsia. Int J Mol Med. 2007;20:717–23.

    PubMed  CAS  Google Scholar 

  41. Wray RN, James MR, Gordon SD, Dumenil T, Ryan L, Coventry WL, et al. Accurate, large-scale genotyping of 5HTTLPR and flanking single nucleotide polymorphisms in an association study of depression, anxiety, and personality measures. Biol Psychiatry. 2009;66:468–76.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

None of the authors have any financial relationship with the organization that sponsored the research. The authors hereby certify that none of the material in this manuscript has been or will be published elsewhere and none is currently under consideration for publication elsewhere.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa, 920-0293, Japan

    Tomiyasu Arisawa, Tomoki Fukuyama, Ranji Hayashi, Kazuhiro Matsunaga, Nobuhiko Hayashi, Masakatsu Nakamura, Nobuyuki Toshikuni & Hisakazu Shiroeda

  2. Department of Gastroenterology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan

    Tomomitsu Tahara & Tomoyuki Shibata

Authors
  1. Tomiyasu Arisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomomitsu Tahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomoki Fukuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ranji Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazuhiro Matsunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobuhiko Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masakatsu Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nobuyuki Toshikuni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hisakazu Shiroeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tomoyuki Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomiyasu Arisawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arisawa, T., Tahara, T., Fukuyama, T. et al. Genetic polymorphism of pri-microRNA 325, targeting SLC6A4 3′-UTR, is closely associated with the risk of functional dyspepsia in Japan. J Gastroenterol 47, 1091–1098 (2012). https://doi.org/10.1007/s00535-012-0576-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-012-0576-1

Keywords

Search

Navigation