Genotypes of Pain and Analgesia in a Randomized Trial of Irritable Bowel Syndrome.
Genotypes of Pain and Analgesia in a Randomized Trial of Irritable Bowel Syndrome.
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DOI：
10.3389/fpsyt.2022.842030
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发表时间：
2022
影响因子：
4.7
通讯作者：
Silvester JA
中科院分区：
文献类型：
--
作者：
Vollert J;Wang R;Regis S;Yetman H;Lembo AJ;Kaptchuk TJ;Cheng V;Nee J;Iturrino J;Loscalzo J;Hall KT;Silvester JA
肠易激综合征（IBS）是一种高度流行的慢性疼痛疾病，具有多种潜在机制，很少有治疗方法在安慰剂对照试验中被证明是有效的。一个潜在的原因可能是使用复合结局，例如IBS症状严重程度量表（IBS-SSS），其中包括与疼痛频率和疼痛强度以及肠功能障碍和腹胀相关的描述性项目。我们调查了IBS疼痛的不同特征是否具有不同的遗传关联，以及这些特征是否可能受到性激素的调节。参加临床试验的中重度IBS（IBS-SSS>175）成人门诊患者在基线和治疗6周后报告了IBS-SSS。使用固定效应模型来测试COMT rs 4680基因型对IBS治疗从基线至第6周的疼痛严重程度（评分为0-100）和疼痛频率（定义为过去10天内疼痛的天数）变化的影响。还进行了平行的探索性全基因组关联研究（GWAS），以确定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，COMT rs 4680 met等位基因与试验过程中疼痛严重程度降低相关[beta（SE）−5.9（2.6），P = 0.028]。用于疼痛频率变化的探索性GWAS在18号染色体上靠近L3 MBTL 4的位置鉴定出5个SNP，其达到全基因组显著性（所有P < 5.0E-8）。这种效应不是通过改变雌二醇水平来介导的。7号染色体上也有一个区域，其中24个SNP在全基因组范围内对疼痛严重程度的变化具有提示意义（所有P < 1.0E-5）。先前报道的COMT rs 4680基因型与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（SNX 13）和疼痛频率（L3 MBTL 4）变化相关的新候选基因。需要进一步的研究来了解这些协会和IBS-SSS的不同组成部分的遗传决定因素。ClinicalTrials.gov，标识符：NCT 0280224。
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 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. A 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). Previously 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.
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影响因子：
3.5
作者：
Patel, SM;Stason, WB;Lembo, AJ
通讯作者：
Lembo, AJ
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15.9
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Martin, Loren J.;Smith, Shad B.;Diatchenko, Luda
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Diatchenko, Luda
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Hirata T;Koga K;Johnson TA;Morino R;Nakazono K;Kamitsuji S;Akita M;Kawajiri M;Kami A;Hoshi Y;Tada A;Ishikawa K;Hine M;Kobayashi M;Kurume N;Fujii T;Kamatani N;Osuga Y
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Osuga Y
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9.8
作者：
Lee, OY;Mayer, EA;Naliboff, B
通讯作者：
Naliboff, B
影响因子：
2
作者：
Olafsdottir LB;Gudjonsson H;Jonsdottir HH;Björnsson E;Thjodleifsson B
通讯作者：
Thjodleifsson B