NUDT15 C415T variant compared with TPMT genotyping in predicting azathioprine‐induced leucopenia: prospective analysis of 1014 inflammatory bowel disease patients in India

Abstract

SummaryBackgroundRecent studies reported that Nudix Hydrolase 15(NUDT 15) gene variant (C415T) can better predict thiopurine induced leucopenia in Asian patients with inflammatory bowel disease (IBD) than thiopurine S‐methyl transferase (TPMT).AimTo evaluate the role of the NUDT variant compared with TPMT in predicting azathioprine induced leucopenia in Indian IBD patients.MethodsProspectively collected data of consecutive patients treated with azathioprine from a large IBD registry were analysed for side effects, discontinuation time, and initial and maximum dose tolerated. Genotyping of NUDT15 C415T (rs116855232; p.R139C) was carried out retrieving blood samples from bio‐repository employing real time polymerase chain reaction with age and sex‐matched healthy volunteers. The association of NUDT15 C415T with leucopenia (<3 × 109/L) and neutropenia (<1.5 × 109/L) was evaluated. TPMT genotyping was done in patients who developed leucopenia.ResultsAmong 1014 patients (mean age 35.84 ± 12.74 years; 61% males; 54% ulcerative colitis, 44% Crohn's disease and 2% IBD‐unclassified), 79 were excluded due to inadequate blood samples. Of the remaining 935, 81 (9%) developed leucopenia and 70 (7.5%) developed neutropenia. The variant “T” allele [heterozygous (CT) and homozygous (TT) versus wild type (CC)] was associated with a 19‐fold higher odds (OR19.35, 95% CI11.55‐32.42; P < 0.0001) of leucopenia and 21‐fold higher odds of neutropenia (OR21.41, 95% CI12.25‐37.41). There was significant difference in median dose tolerated between CC, CT and TT (1.35, 1.38 and 0.92 mg/kg body weight, respectively) (P = 0.037) and median duration of therapy (18, 15 and 10 months for CC/CT/TT) (P = 0.003). NUDT15 genotype was an independent risk factor for leucopenia (hazard ratio (HR): CT 11.31, 95% CI6.85‐18.03, P < 0.0001 and TT 31.283, 95% CI14.76‐66.30 compared to CC) and neutropenia (HR: CT 13.04, 95% CI7.65‐22.22, P < 0.0001 and TT 43.39, 95% CI20.21‐92.68 compared to CC). The sensitivities for predicting leucopenia and neutropenia by number of mutant NUDT 15 alleles based on additive predictive model were 66.67% and 70% with a receptor operator characteristic curve area under curve value of 0.791 and 0.807, respectively. Among patients with leucopenia, only 6.2% were heterozygous and none were homozygous for TPMT variants.ConclusionNUDT15 variant genotyping appears to be a better predictor for azathioprine‐induced leucopenia in an Indian population than TPMT with high accuracy and can be useful in optimizing azathioprine dosage.