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

Abstract

BackgroundIrritable 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 SettingAdult 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.MethodsFixed effects modeling was used to test the effect of COMT 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.ResultsA total of 212 participants (74% female) were included. The COMT 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), P = 0.028]. Exploratory GWAS for change in pain frequency identified 5 SNPs in close proximity on chromosome 18 near L3MBTL4 which reached genome-wide significance (all P < 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 P < 1.0E-5).ConclusionsPreviously reported association between COMT 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 (SNX13) and pain frequency (L3MBTL4) 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.

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

“… 151 Recently, investigators identified new candidate genes involved in degradation of epidermal growth factor ( SNX13 ) and histone methyl-lysine binding protein ( L3MBTL4 ) that were associated pain severity and frequency in IBS. 152 The reader is referred to a prior paper that provides an in-depth review on the genetics of visceral sensation in IBS. 27 Focused genomic studies have also implicated SERT gene ( SLC6A4 ) polymorphisms in visceral hypersensitivity in IBS.…”

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

“…Genome-wide studies of both the host and the microbiota have identified variants in several human genes that are responsible for signaling, immunity, and epithelial-function which can in turn have a significant impact on overall gut microbial composition ( Seregin et al, 2017 ; Imhann et al, 2018 ; Hu et al, 2021 ). Recent studies have also identified several genetic variants within individuals that can predispose a host to the onset of disease, such as IBS and IBD, and which are furthermore linked to increased visceral pain ( Bonfiglio et al, 2021 ; Ledergerber et al, 2021 ; Vollert et al, 2022 ). A full discussion of these genetic alterations are beyond the scope of this review, however, a full discussion on host genetics and the microbiota in IBD was recently published by Qiu et al (2022) .…”