Digestive Diseases and Sciences

, Volume 57, Issue 10, pp 2650–2657 | Cite as

The Role of 5-HTT LPR and GNβ3 825C>T Polymorphisms and Gene–Environment Interactions in Irritable Bowel Syndrome (IBS)

  • Yuri A. SaitoEmail author
  • Joseph J. Larson
  • Elizabeth J. Atkinson
  • Euijung Ryu
  • Ann E. Almazar
  • Gloria M. Petersen
  • Nicholas J. Talley
Original Article



Smaller studies have evaluated SLC6A4 5-HTTLPR and GNβ3 825C>T polymorphisms in IBS, and interactions between 5-HTT LPR with life events have been reported in the psychiatric literature, but gene–environment studies in IBS are lacking.


The purpose of this study was to assess the association of two polymorphisms with IBS and age of onset, and whether there are gene–environment interactions with IBS.


Outpatients with IBS and controls completed a validated questionnaire and provided blood for DNA. Comparisons of genotype/allele frequencies between cases and controls were performed with logistic regression. Linear regression was used to evaluate the association between the variants and age of onset. Environmental variables tested included abuse, parental alcohol abuse, parental psychiatric disorders, and gastrointestinal infections.


Genotyping was performed in 385 cases and 262 controls with median age of 50 years (range, 18.0–70.0) and 498 (77 %) females. The IBS subtype distribution among cases was: 102 (26 %) D-IBS, 40 (10 %) C-IBS, 125 (32 %) M-IBS, 118 (31 %) other. No association was observed between IBS or age of onset and both variants. Significant interactions were observed between GI infection and the GNβ3 825T allele. For those reporting gastrointestinal infection, the OR for IBS was 3.9 (95 % CI 1.2–12.7) whereas the OR was 0.86 (95 % CI 0.65–1.13) for those without prior infection.


There was a significant interaction between the GNβ3 polymorphism and infection in the development of IBS, suggesting that its etiology is the result of a combination of specific genetic and environmental risk factors.


Irritable bowel syndrome Genes Genetics Infection 



This study was supported in part by research grants from the National Institutes of Health (K23 DK66271), the American Gastroenterological Association, and Solvay Pharmaceuticals.

Conflict of interest



  1. 1.
    Saito YA, Zimmerman JM, Harmsen WS, et al. Irritable bowel syndrome aggregates strongly in families: a family-based case-control study. Neurogastroenterol Motil. 2008;20:790–797.CrossRefPubMedGoogle Scholar
  2. 2.
    Locke GR III, Zinsmeister AR, Talley NJ, Fett SL, Melton LJ III. Familial association in adults with functional gastrointestinal disorders. Mayo Clin Proc. 2000;75:907–912.CrossRefPubMedGoogle Scholar
  3. 3.
    Whorwell PJ, McCallum M, Creed FH, Roberts CT. Non-colonic features of irritable bowel syndrome. Gut. 1986;27:37–40.CrossRefPubMedGoogle Scholar
  4. 4.
    Mohammed I, Cherkas LF, Riley SA, Spector TD, Trudgill NJ. Genetic influences in irritable bowel syndrome: a twin study. Am J Gastroenterol. 2005;100:1340–1344.CrossRefPubMedGoogle Scholar
  5. 5.
    Morris-Yates A, Talley NJ, Boyce PM, Nandurkar S, Andrews G. Evidence of a genetic contribution to functional bowel disorder. Am J Gastroenterol. 1998;93:1311–1317.CrossRefPubMedGoogle Scholar
  6. 6.
    Bengtson MB, Ronning T, Vatn MH, Harris JR. Irritable bowel syndrome in twins: genes and environment. Gut. 2006;55:1754–1759.CrossRefPubMedGoogle Scholar
  7. 7.
    Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology. 2001;121:799–804.CrossRefPubMedGoogle Scholar
  8. 8.
    Saito YA, Petersen GM, Locke GR 3rd, Talley NJ. The genetics of irritable bowel syndrome. Clin Gastroenterol Hepatol. 2005;3:1057–1065.CrossRefPubMedGoogle Scholar
  9. 9.
    Camilleri CE, Carlson PJ, Camilleri M, et al. A study of candidate genotypes associated with dyspepsia in a U.S. Community. Am J Gastroenterol. 2006;101:593–595.CrossRefGoogle Scholar
  10. 10.
    Holtmann G, Siffert W, Haag S, et al. G-protein beta 3 subunit 825 cc genotype is associated with unexplained (functional) dyspepsia. Gastroenterology. 2004;126:971–979.CrossRefPubMedGoogle Scholar
  11. 11.
    Vergne DE, Nemeroff CB. The interaction of serotonin transporter gene polymorphisms and early adverse life events on vulnerability for major depression. Curr Psychiatry Rep. 2006;8:452–457.CrossRefPubMedGoogle Scholar
  12. 12.
    Serretti A, Chiesa A, Calati R, Perna G, Bellodi L, De Ronchi D. Common genetic, clinical, demographic and psychosocial predictors of response to pharmacotherapy in mood and anxiety disorders. Int Clin Psychopharmacol. 2009;24:1–18.CrossRefPubMedGoogle Scholar
  13. 13.
    Fukudo S, Kanazawa M, Mizuno T, et al. Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention. NeuroImage. 2009;47:946–951.CrossRefPubMedGoogle Scholar
  14. 14.
    Camilleri M, Atanasova E, Carlson PJ, et al. Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2002;123:425–432.CrossRefPubMedGoogle Scholar
  15. 15.
    Van Kerkhoven LA, Laheij RJ, Jansen JB. 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;26:979–986.CrossRefPubMedGoogle Scholar
  16. 16.
    Brown GW, Harris TO. Depression and the serotonin transporter 5-httlpr polymorphism: a review and a hypothesis concerning gene-environment interaction. J Affect Disord. 2008;111:1–12.CrossRefPubMedGoogle Scholar
  17. 17.
    Rosskopf D, Busch S, Manthey I, Siffert W. G protein beta 3 gene: structure, promoter, and additional polymorphisms. Hypertension. 2000;36:33–41.CrossRefPubMedGoogle Scholar
  18. 18.
    Lee HJ, Cha JH, Ham BJ, et al. Association between a g-protein beta3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders. Pharmacogenom J. 2004;4:29–33.CrossRefGoogle Scholar
  19. 19.
    Lindemann M, Virchow S, Ramann F, et al. The G protein beta3 subunit 825T allele is a genetic marker for enhanced T cell response. FEBS Lett. 2001;495:82–86.CrossRefPubMedGoogle Scholar
  20. 20.
    Camilleri M, Busciglio I, Carlson P, et al. Candidate adrenergic, GMβ3, and serotonergic polymorphisms, endophenotype, pharmacogenetics of clonidine in irritable bowel syndrome and health. Gastroenterology 2008;134:A-682.Google Scholar
  21. 21.
    Andresen V, Camilleri M, Kim HJ, et al. Is there an association between GMβ3-C825T genotype and lower functional gastrointestinal disorders? Gastroenterology. 2006;130:1985–1994.CrossRefPubMedGoogle Scholar
  22. 22.
    Thabane M, Kottachchi D, Marshall J. Systematic review and meta-analysis: the incidence and prognosis of post-infectious irritable bowel syndrome. Aliment Pharmacol Ther. 2007;26:535–544.CrossRefPubMedGoogle Scholar
  23. 23.
    Thompson WG, Creed FH, Drossman DA, Heaton KW, Mazzacca G. Functional bowel disease and functional abdominal pain. Gastrenterol Int. 1992;5:75–91.Google Scholar
  24. 24.
    Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muller-Lissner SA. Functional bowel disorders and functional abdominal pain. Gut 1999;45:II43–II47.Google Scholar
  25. 25.
    Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480–1491.CrossRefPubMedGoogle Scholar
  26. 26.
    Talley NJ, Phillips SF, Wiltgen CM, Zinsmeister AR, Melton LJ III. Assessment of functional gastrointestinal disease: the bowel disease questionnaire. Mayo Clin Proc. 1990;65:1456–1479.CrossRefPubMedGoogle Scholar
  27. 27.
    Attanasio V, Andrasik F, Blanchard EB, Arena JG. Psychometric properties of the SUNYA revision of the psychosomatic symptom checklist. J Behav Med. 1984;7:247–257.CrossRefPubMedGoogle Scholar
  28. 28.
    Beck AT, Steer RA. Manual for the Beck Anxiety Inventory. San Antonio: Psychological Corporation; 1990.Google Scholar
  29. 29.
    Haringsma R, Engels GI, Beekman AT, Spinhoven P. The criterion validity of the center for epidemiological studies depression scale (CES-D) in a sample of self-referred elders with depressive symptomatology. Int J Geriatr Psychiatry. 2004;19:558–563.CrossRefPubMedGoogle Scholar
  30. 30.
    Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 1998;43:400–411.CrossRefPubMedGoogle Scholar
  31. 31.
    Drossman DA, Patrick DL, Whitehead WE, et al. Further validation of the IBS-QOL: a disease-specific quality-of-life questionnaire. Am J Gastroenterol. 2000;95:999–1007.CrossRefPubMedGoogle Scholar
  32. 32.
    Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274:1527–1531.CrossRefPubMedGoogle Scholar
  33. 33.
    Siffert W, Forster P, Jockel KH, et al. Worldwide ethnic distribution of the g protein beta3 subunit 825t allele and its association with obesity in Caucasian, Chinese, and black African individuals. J Am Soc Nephrol. 1999;10:1921–1930.PubMedGoogle Scholar
  34. 34.
    Locke GR, 3rd, Zinsmeister AR, Fett SL, Melton LJ, 3rd, Talley NJ. Overlap of gastrointestinal symptom complexes in a U.S. community. Neurogastroenterol Motil. 2005;17:29–34.Google Scholar
  35. 35.
    Virchow S, Ansorge N, Rubben H, Siffert G, Siffert W. Enhanced fMLP-stimulated chemotaxis in human neutrophils from individuals carrying the G protein beta3 subunit 825 T-allele. FEBS Lett. 1998;436:155–158.CrossRefPubMedGoogle Scholar
  36. 36.
    Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002;122:1140–1156.CrossRefPubMedGoogle Scholar
  37. 37.
    Talley NJ, Howell S, Poulton R. The irritable bowel syndrome and psychiatric disorders in the community: is there a link? Am J Gastroenterol. 2001;96:1072–1079.CrossRefPubMedGoogle Scholar
  38. 38.
    Drossman DA. Irritable bowel syndrome and sexual/physical abuse history. Eur J Gastroenterol Hepatol. 1997;9:327–330.CrossRefPubMedGoogle Scholar
  39. 39.
    Gray GC, Reed RJ, Kaiser KS, Smith TC, Gastanaga VM. Self-reported symptoms and medical conditions among 11,868 Gulf War-era veterans: the Seabee Health Study. Am J Epidemiol. 2002;155:1033–1044.CrossRefPubMedGoogle Scholar
  40. 40.
    Hudson JI, Mangweth B, Pope HG Jr, et al. Family study of affective spectrum disorder. Arch Gen Psychiatry. 2003;60:170–177.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Yuri A. Saito
    • 1
    Email author
  • Joseph J. Larson
    • 2
  • Elizabeth J. Atkinson
    • 2
  • Euijung Ryu
    • 2
  • Ann E. Almazar
    • 1
  • Gloria M. Petersen
    • 3
  • Nicholas J. Talley
    • 1
    • 4
  1. 1.Division of Gastroenterology and HepatologyMayo ClinicRochesterUSA
  2. 2.Division of Biomedical Statistics and InformaticsMayo ClinicRochesterUSA
  3. 3.Division of EpidemiologyMayo ClinicRochesterUSA
  4. 4.Faculty of HealthUniversity of NewcastleCallaghanAustralia

Personalised recommendations