Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease
Kaoru Suzuki, Yoichi Kakuta, Takeo Naito, Tetsuya Takagawa, Hiroyuki Hanai, Hiroshi Araki, Yu Sasaki, Hirotake Sakuraba, Makoto Sasaki, Tadakazu Hisamatsu, Satoshi Motoya, Takayuki Matsumoto, Motoyuki Onodera, Yoh Ishiguro, Hiroshi Nakase, Akira Andoh, Sakiko Hiraoka, Masaru Shinozaki, Toshimitsu Fujii, Takehiko Katsurada, Taku Kobayashi, Mikihiro Fujiya, Takafumi Otsuka, Naoki Oshima, Yasuo Suzuki, Yuichirou Sato, Ryota Hokari, Mitsunori Noguchi, Yuki Ohta, Minoru Matsuura, Yosuke Kawai, Katsushi Tokunaga, Masao Nagasaki, Hisaaki Kudo, Naoko Minegishi, Daisuke Okamoto, Yusuke Shimoyama, Rintaro Moroi, Masatake Kuroha, Hisashi Shiga, Dalin Li, Dermot McGovern, Yoshitaka Kinouchi, Atsushi Masamune, MENDEL study group, Kentaro Ikeya, Atsushi Nishida, Shoko Nakagawa, Miki Miura, Takahiko Toyonaga, Kei Onodera, Masahiro Takahara, Shunichi Yanai, Shunji Ishihara, Masakazu Nagahori, Katsuyoshi Matsuoka, Katsuhiro Arai, Shinta Mizuno, Makoto Naganuma, Shirô Nakamura, Tomoaki Ishikawa, Hiroki Nakajima, Hiroshi Terasaki, Rumiko Saito, Isao Amemiya, Hideaki Ohyama, Kai Korekawa, Hideya Iwaki, Sayumi Takahashi, Motoki Makuuchi, Yushi Inomata, Fumiko Shimoda, Takahiro Takahashi, Kota Yano, I. Abe, Tomoyuki Handa, Yutaro Masu, Kasumi Hishinuma, Yoshitake Kanazawa, Tomoya Kimura, Kenichi Negoro, Mai Kato
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.