Abstract
BackgroundDespite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.MethodsOverall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.ResultsWe confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E−63, 1.32E−69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E−04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively).ConclusionsGenotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.
Highlights
The thiopurine drug 6-mercaptopurine (6-MP) and its prodrug azathiopurine (AZA) are most commonly used for immunomodulatory treatments for inflammatory bowel disease (IBD), represented by ulcerative colitis (UC), Crohn’s disease (CD), and intestinal Behcet’s disease (BD) [1]
Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and genomewide association study (GWAS) of adverse events (AEs) were performed with 1221 patients using populationoptimized genotyping array and imputation
Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively)
Summary
The thiopurine drug 6-mercaptopurine (6-MP) and its prodrug azathiopurine (AZA) are most commonly used for immunomodulatory treatments for inflammatory bowel disease (IBD), represented by ulcerative colitis (UC), Crohn’s disease (CD), and intestinal Behcet’s disease (BD) [1]. The most common but serious AE is leukopenia, so doctors need to frequently monitor white blood cell (WBC) counts during the initiation period. It is not life-threatening, severe alopecia may occur, and it results in a very serious event causing cosmetic problems requiring long recovery period. 11 Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan. J Gastroenterol (2018) 53:1065–1078 of NUDT15 variants and haplotypes with AEs, genomewide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs. Methods Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. Methods Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using populationoptimized genotyping array and imputation
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