Vollert Jan, Wang Ruisheng, Regis Stephanie, Yetman Hailey, Lembo Anthony J, Kaptchuk Ted J, Cheng Vivian, Nee Judy, Iturrino Johanna, Loscalzo Joseph, Hall Kathryn T, Silvester Jocelyn A
Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.
Department of Neurology, University Hospital of Schleswig-Holstein, Kiel, Germany.
Front Psychiatry. 2022 Mar 23;13:842030. doi: 10.3389/fpsyt.2022.842030. eCollection 2022.
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.
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.
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.
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).
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.
肠易激综合征（IBS）是一种高度流行的慢性疼痛疾病，其潜在机制多样，在安慰剂对照试验中被证明有效的治疗方法很少。一个潜在原因可能是使用了综合结果指标，如肠易激综合征症状严重程度量表（IBS-SSS），该量表包括与疼痛频率、疼痛强度以及肠道功能障碍和腹胀相关的描述性项目。我们研究了IBS疼痛的不同特征是否具有独特的基因关联，以及这些关联是否可能受到性激素的调节。
参加一项临床试验的成年门诊中重度IBS患者（IBS-SSS评分>175）在基线时和治疗6周后报告了IBS-SSS评分。
采用固定效应模型，测试rs4680基因型对IBS治疗从基线到第6周疼痛严重程度变化（0-100分评分）和疼痛频率（定义为过去10天中有疼痛的天数）的影响。还进行了平行探索性全基因组关联研究（GWAS），以识别所有参与者中与疼痛严重程度或疼痛频率变化相关的单核苷酸多态性（SNP）。
共纳入212名参与者（74%为女性）。在基因剂量模型中，rs4680的met等位基因与试验过程中疼痛严重程度的降低相关[β（标准误）-5.9（2.6），P = 0.028]。对疼痛频率变化的探索性GWAS在18号染色体上靠近的位置发现了5个紧密相邻的SNP，达到全基因组显著性水平（所有P < 5.0E-8）。这种效应不是由雌二醇水平的变化介导的。在7号染色体上也有一个区域，有24个SNP对疼痛严重程度变化具有全基因组提示性显著性（所有P < 1.0E-5）。
先前报道的rs4680基因型与通过IBS-SSS测量的治疗反应之间的关联与疼痛严重程度有关，但与疼痛频率无关。我们还确定了与IBS疼痛严重程度（）和疼痛频率（）对治疗反应变化相关的新候选基因。需要进一步研究以了解这些关联以及IBS-SSS不同组成部分的遗传决定因素。ClinicalTrials.gov标识符：NCT0280224。
