Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease
Authors: 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 ,   MENDEL study group, Ikeya Kentaro , Nishida Atsushi , Nakagawa Shoko , Miura Miki , Toyonaga Takahiko , Onodera Kei , Takahara Masahiro , Yanai Shunichi , Ishihara Shunji , Nagahori Masakazu , Matsuoka Katsuyoshi , Arai Katsuhiro , Mizuno Shinta , Naganuma Makoto , Nakamura Shiro , Ishikawa Tomoaki , Nakajima Hiroki , Terasaki Hiroshi , Saito Rumiko , Amemiya Isao , Ohyama Hideaki , Korekawa Kai , Iwaki Hideya , Takahashi Sayumi , Makuuchi Motoki , Inomata Yushi , Shimoda Fumiko , Takahashi Takahiro , Yano Kota , Abe Izuru , Handa Tomoyuki , Masu Yutaro , Hishinuma Kasumi , Kanazawa Yoshitake , Kimura Tomoya , Negoro Kenichi , Kato Mai 
Published: January 2021

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.