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

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.

Personalized medicine in inflammatory bowel disease: Perspectives on Asia

“…A recent Japanese study that was undertaken to select patients with IBD and a high possibility of 5-ASA allergy analyzed the genetic backgrounds of patients with 5-ASA intolerance using a pharmacogenomic approach. 122 5-ASA allergy was found to be more common in patients with UC than in those with CD and was associated with rs144384547 (upstream of RGS17) in this GWAS and meta-analysis (odds ratio, 11.2; P = 7.21e-09).…”

“…A 5‐ASA allergic reaction, represented clinically as high fever and worsening diarrhea, occurs in patients with IBD receiving 5‐ASA, and a method in which to predict the clinical outcome has not been established. A recent Japanese study that was undertaken to select patients with IBD and a high possibility of 5‐ASA allergy analyzed the genetic backgrounds of patients with 5‐ASA intolerance using a pharmacogenomic approach 122 . 5‐ASA allergy was found to be more common in patients with UC than in those with CD and was associated with rs144384547 (upstream of RGS17) in this GWAS and meta‐analysis (odds ratio, 11.2; P = 7.21e‐09).…”

A Systematic Review and Analysis of the Use of Polygenic Scores in Pharmacogenomics

“…A number of conditions were covered in the remaining 14 publications included in this review. Three articles examined PGSs in the context of the treatment of inflammatory bowel disease, with one of these studies reporting a significant association between mesalamine‐induced allergy and a PGS based on a small GWAS of this ADR 62‐64 . Similarly, three articles were focused on the treatment of neoplasms, with one of these articles reporting a significant association between PGSs derived from GWASs of vitiligo, psoriasis, and atopic dermatitis and overall survival of bladder cancer in atezolizumab‐treated patients 65‐67 .…”

“…mesalamine-induced allergy and a PGS based on a small GWAS of this ADR. [62][63][64] Similarly, three articles were focused on the treatment of neoplasms, with one of these articles reporting a significant association between PGSs derived from GWASs of vitiligo, psoriasis, and atopic dermatitis and overall survival of bladder cancer in atezolizumab-treated patients. [65][66][67] The remaining articles were focused on various efficacy phenotypes (response to antidiabetic medications, 39 growth hormones, 39,68 migraine therapeutics, 40 and Kawasaki disease treatments 69 ) and ADR phenotypes (drug-induced liver injury, 44 levodopa-induced dyskinesias, 70 drug-induced fractures, 44,71 and antiretroviral-induced weight gain 72 ).…”

Validity of Diagnostic Algorithms for Inflammatory Bowel Disease in Japanese Hospital Claims Data

“…In addition, side-effects of drugs for IBD have been reported, including mesalamine intolerance [5][6][7], allergic reactions to biological medicine [8], and thiopurine-induced leukopenia and alopecia [9,10]. For thiopurine, side effects can be avoided by examining NUDT15 codon 139 [9,11,12], but there is still no clear way to avoid side effects with other drugs.…”