Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease
Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease
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DOI：
10.1093/ibd/izab004
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发表时间：
2021-01-27
影响因子：
4.9
通讯作者：
Masamune, Atsushi
中科院分区：
文献类型：
--
作者：
Suzuki, Kaoru;Kakuta, Yoichi;Masamune, Atsushi
背景资料：一些患有炎症性肠病（IBD）的患者在接受美沙拉嗪治疗时会出现称为“美沙拉嗪过敏”的不良反应，包括高烧和腹泻恶化。目前，还没有方法来预测美沙拉嗪过敏。药物基因组学方法可能有助于识别这些患者。在这里，我们分析了美沙拉嗪不耐受的遗传背景，在第一个全基因组关联研究的日本IBD.Methods患者：两个独立的药物遗传学IBD队列进行了分析：MENDEL（n = 1523;作为一个发现集）和东北（n = 788;作为一个复制集）队列。在每个人群中进行全基因组关联研究，然后进行荟萃分析。此外，我们构建了一个多基因的风险评分模型，并结合遗传和临床因素来模拟美沙拉嗪intolerance.Results：在合并队列中，美沙拉嗪引起的发热和/或腹泻是显着更频繁的溃疡性结肠炎与克罗恩病。全基因组关联研究和荟萃分析确定了rs 144384547（RGS 17上游）与美沙拉嗪诱导的发热和腹泻之间的显著关联（P = 7.21e-09;比值比= 11.2）。美沙拉嗪过敏的估计遗传率为25.4%，表明与遗传背景有显著相关性。此外，建立了多基因风险评分模型来预测美沙拉嗪过敏（P = 2.95e-2）。联合遗传/临床预测模型产生了更高的曲线下面积比多基因风险评分或单独的临床模型（曲线下面积，0.89;敏感性，71.4%;特异性，90.8%）。结论：美沙拉嗪过敏是更常见的溃疡性结肠炎比克罗恩病。我们确定了一种新的遗传相关性，并为该不良事件开发了一种联合临床/遗传模型。
Background: Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy," which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD.Methods: Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance.Results: In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%).Conclusions: Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.