Genotypes of Pain and Analgesia in a Randomized Trial of Irritable Bowel Syndrome

Overview

Journal Front Psychiatry

Specialty Psychiatry

Date 2022 Apr 11

PMID 35401282

Authors

Jan Vollert

Ruisheng Wang

Stephanie Regis

Hailey Yetman

Anthony J Lembo

Ted J Kaptchuk

Vivian Cheng

Judy Nee

Johanna Iturrino

Joseph Loscalzo

Kathryn T Hall

Jocelyn A Silvester

Affiliations

Soon will be listed here.

Abstract

Background: Irritable bowel syndrome (IBS) is a highly prevalent chronic pain disorder with multiple underlying mechanisms and few treatments that have been demonstrated to be effective in placebo controlled trials. One potential reason may be the use of composite outcomes, such as the IBS Symptom Severity Scale (IBS-SSS) which includes descriptive items related to pain frequency and pain intensity as well as bowel dysfunction and bloating. We investigated if different features of IBS pain have distinct genetic associations and if these may be moderated by sex hormones.

Participants And Setting: Adult outpatients with moderately severe IBS (>175 on IBS-SSS) enrolled in a clinical trial reported IBS-SSS at baseline and after 6 weeks of therapy.

Methods: Fixed effects modeling was used to test the effect of rs4680 genotype to change in pain severity (rated 0-100) and pain frequency (defined as number of days with pain in the past 10 days) from baseline to week 6 with IBS treatment. Parallel exploratory genome-wide association studies (GWAS) were also performed to identify single nucleotide polymorphisms (SNPs) associated with change in pain severity or pain frequency across all participants.

Results: A total of 212 participants (74% female) were included. The rs4680 met allele was associated with decreased pain severity over the course of the trial in gene dosage models [beta(SE) -5.9 (2.6), = 0.028]. Exploratory GWAS for change in pain frequency identified 5 SNPs in close proximity on chromosome 18 near which reached genome-wide significance (all < 5.0E-8). This effect was not mediated by changing estradiol levels. There was also a region of chromosome 7 with 24 SNPs of genome-wide suggestive significance for change in pain severity (all < 1.0E-5).

Conclusions: Previously reported association between rs4680 genotype and treatment response as measured by IBS-SSS is related to pain severity, but not pain frequency. We also identified new candidate genes associated with changes in IBS pain severity () and pain frequency () in response to treatment. Further studies are needed to understand these associations and genetic determinants of different components of IBS-SSS. ClinicalTrials.gov, Identifier: NCT0280224.

Citing Articles

Multi-omics for biomarker approaches in the diagnostic evaluation and management of abdominal pain and irritable bowel syndrome: what lies ahead.

Shin A, Kashyap P Gut Microbes. 2023; 15(1):2195792.

PMID: 37009874 PMC: 10072066. DOI: 10.1080/19490976.2023.2195792.

Metabolomics: The Key to Unraveling the Role of the Microbiome in Visceral Pain Neurotransmission.

Shute A, Bihan D, Lewis I, Nasser Y Front Neurosci. 2022; 16:917197.

PMID: 35812241 PMC: 9260117. DOI: 10.3389/fnins.2022.917197.

References

Spiegel B, Bolus R, Harris L, Lucak S, Naliboff B, Esrailian E . Measuring irritable bowel syndrome patient-reported outcomes with an abdominal pain numeric rating scale. Aliment Pharmacol Ther. 2009; 30(11-12):1159-70. PMC: 2793273. DOI: 10.1111/j.1365-2036.2009.04144.x. View

Yu R, Gollub R, Vangel M, Kaptchuk T, Smoller J, Kong J . Placebo analgesia and reward processing: integrating genetics, personality, and intrinsic brain activity. Hum Brain Mapp. 2014; 35(9):4583-93. PMC: 4107077. DOI: 10.1002/hbm.22496. View

Olafsdottir L, Gudjonsson H, Jonsdottir H, Bjornsson E, Thjodleifsson B . Natural history of irritable bowel syndrome in women and dysmenorrhea: a 10-year follow-up study. Gastroenterol Res Pract. 2012; 2012:534204. PMC: 3312222. DOI: 10.1155/2012/534204. View

Kim Y, Kim N . Sex-Gender Differences in Irritable Bowel Syndrome. J Neurogastroenterol Motil. 2018; 24(4):544-558. PMC: 6175559. DOI: 10.5056/jnm18082. View

Orrey D, Bortsov A, Hoskins J, Shupp J, Jones S, Cicuto B . Catechol-O-methyltransferase genotype predicts pain severity in hospitalized burn patients. J Burn Care Res. 2012; 33(4):518-23. PMC: 3319634. DOI: 10.1097/BCR.0b013e31823746ed. View

Rastelli D, Robinson A, Lagomarsino V, Matthews L, Hassan R, Perez K . Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice. J Clin Invest. 2021; 132(2). PMC: 8759776. DOI: 10.1172/JCI150789. View

Saito Y, Schoenfeld P, Richard Locke 3rd G . The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002; 97(8):1910-5. DOI: 10.1111/j.1572-0241.2002.05913.x. View

Chey W, Kurlander J, Eswaran S . Irritable bowel syndrome: a clinical review. JAMA. 2015; 313(9):949-58. DOI: 10.1001/jama.2015.0954. View

Freidin M, Stalteri M, Wells P, Lachance G, Baleanu A, Bowyer R . An association between chronic widespread pain and the gut microbiome. Rheumatology (Oxford). 2020; 60(8):3727-3737. PMC: 8328510. DOI: 10.1093/rheumatology/keaa847. View

10.

Lembo A, Kelley J, Nee J, Ballou S, Iturrino J, Cheng V . Open-label placebo vs double-blind placebo for irritable bowel syndrome: a randomized clinical trial. Pain. 2021; 162(9):2428-2435. PMC: 8357842. DOI: 10.1097/j.pain.0000000000002234. View

11.

Wang R, Lembo A, Kaptchuk T, Cheng V, Nee J, Iturrino J . Genomic Effects Associated With Response to Placebo Treatment in a Randomized Trial of Irritable Bowel Syndrome. Front Pain Res (Lausanne). 2022; 2:775386. PMC: 8915627. DOI: 10.3389/fpain.2021.775386. View

12.

Mulak A, Tache Y . Sex difference in irritable bowel syndrome: do gonadal hormones play a role?. Gastroenterol Pol. 2014; 17(2):89-97. PMC: 4244886. View

13.

Hirata T, Koga K, Johnson T, Morino R, Nakazono K, Kamitsuji S . Japanese GWAS identifies variants for bust-size, dysmenorrhea, and menstrual fever that are eQTLs for relevant protein-coding or long non-coding RNAs. Sci Rep. 2018; 8(1):8502. PMC: 5981393. DOI: 10.1038/s41598-018-25065-9. View

14.

Zheng B, Lavoie C, Tang T, Ma P, Meerloo T, Beas A . Regulation of epidermal growth factor receptor degradation by heterotrimeric Galphas protein. Mol Biol Cell. 2004; 15(12):5538-50. PMC: 532032. DOI: 10.1091/mbc.e04-06-0446. View

15.

Patel S, Stason W, Legedza A, Ock S, Kaptchuk T, Conboy L . The placebo effect in irritable bowel syndrome trials: a meta-analysis. Neurogastroenterol Motil. 2005; 17(3):332-40. DOI: 10.1111/j.1365-2982.2005.00650.x. View

16.

Cui X, Zhou W, Yang Y, Zhou J, Li X, Lin L . Epidermal growth factor upregulates serotonin transporter and its association with visceral hypersensitivity in irritable bowel syndrome. World J Gastroenterol. 2014; 20(37):13521-9. PMC: 4188903. DOI: 10.3748/wjg.v20.i37.13521. View

17.

Martin L, Smith S, Khoutorsky A, Magnussen C, Samoshkin A, Sorge R . Epiregulin and EGFR interactions are involved in pain processing. J Clin Invest. 2017; 127(9):3353-3366. PMC: 5669538. DOI: 10.1172/JCI87406. View

18.

Lee O, Mayer E, Schmulson M, Chang L, Naliboff B . Gender-related differences in IBS symptoms. Am J Gastroenterol. 2001; 96(7):2184-93. DOI: 10.1111/j.1572-0241.2001.03961.x. View

19.

Lachman H, Papolos D, Saito T, Yu Y, Szumlanski C, Weinshilboum R . Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996; 6(3):243-50. DOI: 10.1097/00008571-199606000-00007. View

20.

Hall K, Lembo A, Kirsch I, Ziogas D, Douaiher J, Jensen K . Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome. PLoS One. 2012; 7(10):e48135. PMC: 3479140. DOI: 10.1371/journal.pone.0048135. View