NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study

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.Electronic supplementary materialThe online version of this article (10.1007/s00535-018-1486-7) contains supplementary material, which is available to authorized users.

Long‐term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

“…(MENDEL study) reported that the average time to leukopenia (WBC < 3.0 × 10 3 /mm 3 ) in patients with the C/T genotype was 365 ± 573 days. 22 Our study shows that the decrease in WBC count per mg of AZA is comparable from T0 to T1 between the C/C and C/T groups. However, while little decrease in WBC count was observed from T1 to T2 in the C/C group, such a decrease was evident in the C/T group.…”

“…Regarding the onset of leukopenia in patients with the C/T genotype, a Korean study showed that the median interval from thiopurine initiation to leukopenia (WBC < 3.0 × 10 3 /mm 3 ) was 135 (12–3300) days . A large Japanese multicenter study (MENDEL study) reported that the average time to leukopenia (WBC < 3.0 × 10 3 /mm 3 ) in patients with the C/T genotype was 365 ± 573 days . Our study shows that the decrease in WBC count per mg of AZA is comparable from T0 to T1 between the C/C and C/T groups.…”

“…Our study is the first study to demonstrate the long‐term kinetics of WBC count in patients heterozygous for the NUDT15 R139C variant. Previous studies demonstrated a strong association between the NUDT15 R139C genotype and early thiopurine‐induced leukopenia in Asian IBD patients . Kojima et al .…”

“…Previous studies demonstrated a strong association between the NUDT15 R139C genotype and early thiopurine-induced leukopenia in Asian IBD patients. 12,15,16,22,23 Kojima et al observed that compared with patients with the variant, the WBC count became significantly lower at 6 weeks and remained lower through the remainder of the 16-week study period in those with the variant. 23 Although the WBC count beyond 16 weeks was not determined in their study, their WBC results up to this point are consistent with ours.…”

Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD

“…The association of TPMT genotype polymorphisms and TIL was assessed in 31 studies, the association of TPMT enzymatic activity and TIL in 12 (Table S1). …”