Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic Epidemiology and Pharmacogenetics in Irritable Bowel Syndrome

Overview

Journal Am J Physiol Gastrointest Liver Physiol

Publisher American Physiological Society

Specialties Gastroenterology
Physiology

Date 2012 Mar 10

PMID 22403795

Citations 48

Authors

Michael Camilleri

David A Katzka

Affiliations

Soon will be listed here.

Abstract

The objectives of this review are twofold. Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome (IBS). Specific examples of the associations of genetic variation and symptoms, syndromes, and intermediate phenotypes, including neurotransmitter (serotonergic, α(2)-adrenergic, and cannabinoid) mechanisms, inflammatory pathways (IL-10, TNFα, GNβ3, and susceptibility loci involved in Crohn's disease), and bile acid metabolism, are explored. The second objective is to review pharmacogenetics in IBS, with the focus on cytochrome P-450 metabolism of drugs used in IBS, modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine (5-HT) transporter-linked polymorphic region (5-HTTLPR) and 5-HT(3) genetic variants, responses to a nonselective cannabinoid agonist (dronabinol) based on cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) variation, and responses to a bile acid (sodium chenodeoxycholate) and bile acid binding (colesevelam) based on klothoβ (KLB) and fibroblast growth factor receptor 4 (FGFR4) variation. Overall, there is limited evidence of a genetic association with IBS; the most frequently studied association is with 5-HTTLPR, and the most replicated association is with TNF superfamily member 15. Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials, and confirmation in large clinical trials using validated clinical end points is still required. No published genome-wide association studies in functional gastrointestinal or motility disorders have been published.

Citing Articles

Pharmacogenetics in IBS: update and impact of GWAS studies in drug targets and metabolism.

Camilleri M, Jencks K Expert Opin Drug Metab Toxicol. 2024; 20(5):319-332.

PMID: 38785066 PMC: 11139426. DOI: 10.1080/17425255.2024.2349716.

Disruption of the microbiota-gut-brain axis is a defining characteristic of the α-Gal A (-/0) mouse model of Fabry disease.

Delprete C, Rimondini Giorgini R, Lucarini E, Bastiaanssen T, Scicchitano D, Interino N Gut Microbes. 2023; 15(2):2256045.

PMID: 37712629 PMC: 10506438. DOI: 10.1080/19490976.2023.2256045.

The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets.

Maqoud F, Tricarico D, Mallamaci R, Orlando A, Russo F Int J Mol Sci. 2023; 24(13).

PMID: 37446251 PMC: 10342167. DOI: 10.3390/ijms241311074.

Genetics of irritable bowel syndrome: shifting gear via biobank-scale studies.

Camilleri M, Zhernakova A, Bozzarelli I, DAmato M Nat Rev Gastroenterol Hepatol. 2022; 19(11):689-702.

PMID: 35948782 DOI: 10.1038/s41575-022-00662-2.

Sex and Gender Differences in Overlap Syndrome of Functional Gastrointestinal Disorder and Effect of Genetic Polymorphisms in South Korea: A Long-term Follow-up Study.

Lee J, Kim N, Park J, Yu J, Song Y, Yoon J J Neurogastroenterol Motil. 2022; 28(1):145-158.

PMID: 34980697 PMC: 8748849. DOI: 10.5056/jnm21047.

References

Keitel V, Cupisti K, Ullmer C, Knoefel W, Kubitz R, Haussinger D . The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology. 2009; 50(3):861-70. DOI: 10.1002/hep.23032. View

Kalantar J, Locke 3rd G, Zinsmeister A, Beighley C, Talley N . Familial aggregation of irritable bowel syndrome: a prospective study. Gut. 2003; 52(12):1703-7. PMC: 1773907. DOI: 10.1136/gut.52.12.1703. View

Camilleri M, Carlson P, McKinzie S, Grudell A, Busciglio I, Burton D . Genetic variation in endocannabinoid metabolism, gastrointestinal motility, and sensation. Am J Physiol Gastrointest Liver Physiol. 2007; 294(1):G13-9. DOI: 10.1152/ajpgi.00371.2007. View

Spiller R, Garsed K . Postinfectious irritable bowel syndrome. Gastroenterology. 2009; 136(6):1979-88. DOI: 10.1053/j.gastro.2009.02.074. View

Ohman L, Simren M . Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol. 2010; 7(3):163-73. DOI: 10.1038/nrgastro.2010.4. View

Briejer M, Mathis C, Schuurkes J . 5-HT receptor types in the rat ileum longitudinal muscle: focus on 5-HT2 receptors mediating contraction. Neurogastroenterol Motil. 1998; 9(4):231-7. DOI: 10.1046/j.1365-2982.1997.d01-62.x. View

Lee K, Kim Y, Kim J, Kwon H, Kim D, Cho S . The alteration of enterochromaffin cell, mast cell, and lamina propria T lymphocyte numbers in irritable bowel syndrome and its relationship with psychological factors. J Gastroenterol Hepatol. 2009; 23(11):1689-94. DOI: 10.1111/j.1440-1746.2008.05574.x. View

Small K, Wagoner L, Levin A, Kardia S, Liggett S . Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med. 2002; 347(15):1135-42. DOI: 10.1056/NEJMoa020803. View

Tornblom H, Lindberg G, Nyberg B, Veress B . Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology. 2002; 123(6):1972-9. DOI: 10.1053/gast.2002.37059. View

10.

Rao A, Wong B, Camilleri M, Odunsi-Shiyanbade S, McKinzie S, Ryks M . Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis. Gastroenterology. 2010; 139(5):1549-58, 1558.e1. PMC: 3189402. DOI: 10.1053/j.gastro.2010.07.052. View

11.

Ghoshal U, Abraham P, Bhatt C, Choudhuri G, Bhatia S, Shenoy K . Epidemiological and clinical profile of irritable bowel syndrome in India: report of the Indian Society of Gastroenterology Task Force. Indian J Gastroenterol. 2008; 27(1):22-8. View

12.

Camilleri M, Andrews C, Bharucha A, Carlson P, Ferber I, Stephens D . Alterations in expression of p11 and SERT in mucosal biopsy specimens of patients with irritable bowel syndrome. Gastroenterology. 2007; 132(1):17-25. PMC: 2474784. DOI: 10.1053/j.gastro.2006.11.020. View

13.

Bampton P, Dinning P, Kennedy M, Lubowski D, Cook I . The proximal colonic motor response to rectal mechanical and chemical stimulation. Am J Physiol Gastrointest Liver Physiol. 2002; 282(3):G443-9. DOI: 10.1152/ajpgi.00194.2001. View

14.

Saito Y, Mitra N, Mayer E . Genetic approaches to functional gastrointestinal disorders. Gastroenterology. 2010; 138(4):1276-85. PMC: 3829382. DOI: 10.1053/j.gastro.2010.02.037. View

15.

Lesch K, Bengel D, Heils A, Sabol S, Greenberg B, Petri S . Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996; 274(5292):1527-31. DOI: 10.1126/science.274.5292.1527. View

16.

Enoch M, Goldman D, Barnett R, Sher L, Mazzanti C, Rosenthal N . Association between seasonal affective disorder and the 5-HT2A promoter polymorphism, -1438G/A. Mol Psychiatry. 1999; 4(1):89-92. DOI: 10.1038/sj.mp.4000439. View

17.

Parsons M, DSouza U, Arranz M, Kerwin R, Makoff A . The -1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity. Biol Psychiatry. 2004; 56(6):406-10. DOI: 10.1016/j.biopsych.2004.06.020. View

18.

Chiang K, Gerber A, Sipe J, Cravatt B . Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet. 2004; 13(18):2113-9. DOI: 10.1093/hmg/ddh216. View

19.

Camilleri C, Carlson P, Camilleri M, Castillo E, Richard Locke 3rd G, Geno D . A study of candidate genotypes associated with dyspepsia in a U.S. community. Am J Gastroenterol. 2006; 101(3):581-92. DOI: 10.1111/j.1572-0241.2006.00481.x. View

20.

Camilleri M, Nadeau A, Tremaine W, Lamsam J, Burton D, Odunsi S . Measurement of serum 7alpha-hydroxy-4-cholesten-3-one (or 7alphaC4), a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry. Neurogastroenterol Motil. 2009; 21(7):734-e43. PMC: 2705747. DOI: 10.1111/j.1365-2982.2009.01288.x. View