Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease.
Anti-Inflammatory Agents, Non-Steroidal
/ adverse effects
Colitis, Ulcerative
/ chemically induced
Diarrhea
/ chemically induced
Genetic Background
Genome-Wide Association Study
Humans
Inflammatory Bowel Diseases
/ chemically induced
Japan
/ epidemiology
Mesalamine
/ adverse effects
Models, Statistical
Prognosis
RGS Proteins
RGS17
mesalamine
pharmacogenetics
polygenic risk score
Journal
Inflammatory bowel diseases
ISSN: 1536-4844
Titre abrégé: Inflamm Bowel Dis
Pays: England
ID NLM: 9508162
Informations de publication
Date de publication:
05 01 2022
05 01 2022
Historique:
received:
23
12
2020
pubmed:
28
1
2021
medline:
1
4
2022
entrez:
27
1
2021
Statut:
ppublish
Résumé
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. 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. 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%). 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.
Sections du résumé
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.
Identifiants
pubmed: 33501934
pii: 6121230
doi: 10.1093/ibd/izab004
doi:
Substances chimiques
Anti-Inflammatory Agents, Non-Steroidal
0
RGS Proteins
0
RGS17 protein, human
0
Mesalamine
4Q81I59GXC
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
21-31Investigateurs
Kentaro Ikeya
(K)
Atsushi Nishida
(A)
Shoko Nakagawa
(S)
Miki Miura
(M)
Takahiko Toyonaga
(T)
Kei Onodera
(K)
Masahiro Takahara
(M)
Shunichi Yanai
(S)
Shunji Ishihara
(S)
Masakazu Nagahori
(M)
Katsuyoshi Matsuoka
(K)
Katsuhiro Arai
(K)
Shinta Mizuno
(S)
Makoto Naganuma
(M)
Shiro Nakamura
(S)
Tomoaki Ishikawa
(T)
Hiroki Nakajima
(H)
Hiroshi Terasaki
(H)
Rumiko Saito
(R)
Isao Amemiya
(I)
Hideaki Ohyama
(H)
Kai Korekawa
(K)
Hideya Iwaki
(H)
Sayumi Takahashi
(S)
Motoki Makuuchi
(M)
Yushi Inomata
(Y)
Fumiko Shimoda
(F)
Takahiro Takahashi
(T)
Kota Yano
(K)
Izuru Abe
(I)
Tomoyuki Handa
(T)
Yutaro Masu
(Y)
Kasumi Hishinuma
(K)
Yoshitake Kanazawa
(Y)
Tomoya Kimura
(T)
Kenichi Negoro
(K)
Mai Kato
(M)
Informations de copyright
© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.