日本炎症性肠病患者中柳氮磺胺吡啶诱导的发热和腹泻的遗传背景

Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease.

作者信息

Suzuki Kaoru, Kakuta Yoichi, Naito Takeo, Takagawa Tetsuya, Hanai Hiroyuki, Araki Hiroshi, Sasaki Yu, Sakuraba Hirotake, Sasaki Makoto, Hisamatsu Tadakazu, Motoya Satoshi, Matsumoto Takayuki, Onodera Motoyuki, Ishiguro Yoh, Nakase Hiroshi, Andoh Akira, Hiraoka Sakiko, Shinozaki Masaru, Fujii Toshimitsu, Katsurada Takehiko, Kobayashi Taku, Fujiya Mikihiro, Otsuka Takafumi, Oshima Naoki, Suzuki Yasuo, Sato Yuichirou, Hokari Ryota, Noguchi Mitsunori, Ohta Yuki, Matsuura Minoru, Kawai Yosuke, Tokunaga Katsushi, Nagasaki Masao, Kudo Hisaaki, Minegishi Naoko, Okamoto Daisuke, Shimoyama Yusuke, Moroi Rintaro, Kuroha Masatake, Shiga Hisashi, Li Dalin, McGovern Dermot P B, Kinouchi Yoshitaka, Masamune Atsushi

机构信息

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.

F. Widjaja Foundation Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

出版信息

Inflamm Bowel Dis. 2022 Jan 5;28(1):21-31. doi: 10.1093/ibd/izab004.

DOI:10.1093/ibd/izab004

PMID:33501934

Abstract

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.

摘要

背景

一些接受美沙拉嗪治疗的炎症性肠病（IBD）患者会出现被称为“美沙拉嗪过敏”的不良反应，其中包括高热和腹泻加重。目前，尚无预测美沙拉嗪过敏的方法。药物基因组学方法可能有助于识别这些患者。在此，我们在日本IBD患者的首次全基因组关联研究中分析了美沙拉嗪不耐受的遗传背景。

方法

分析了两个独立的药物遗传学IBD队列：MENDEL队列（n = 1523；作为发现集）和东北队列（n = 788；作为验证集）。在每个队列中进行全基因组关联研究，随后进行荟萃分析。此外，我们构建了一个多基因风险评分模型，并结合遗传和临床因素来模拟美沙拉嗪不耐受情况。

结果

在合并队列中，溃疡性结肠炎患者中美沙拉嗪诱发的发热和/或腹泻比克罗恩病患者更常见。全基因组关联研究和荟萃分析确定了rs144384547（RGS17上游）与美沙拉嗪诱发的发热和腹泻之间存在显著关联（P = 7.21e - 09；比值比 = 11.2）。美沙拉嗪过敏的估计遗传度为25.4%，表明与遗传背景存在显著相关性。此外，构建了一个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/临床预测模型的曲线下面积高于单独的多基因风险评分或临床模型（曲线下面积为0.89；敏感性为71.4%；特异性为90.8%）。