Sa1679 - Nudt15 Variant can Predict the Development of Azathioprine Induced Leucopenia and Allow Optimal Dosing in Indian Patients with Inflammatory Bowel Disease (IBD)

Abstract

Background Azathioprine (AZA) is a widely used cost-effective option for maintenance of steroid-free remission of IBD. Leucopenia is a common complication. Recent GWAS studies have identified a strong association between NUDT 15 C415T variant and thiopurine-induced leucopenia in Asia. We assessed the prevalence of NUDT variant and its association with leucopenia and dosing of AZA in an Indian IBD cohort. Methods Prospectively collected data from our IBD Clinic Registry was analysed. 729 consecutive patients treated with AZA were included. The incidence of side effects, initial and maximum dose tolerated and discontinuation time was noted. Blood sample (at-80C) of these patients were retrieved from the biorepository. Age and sex matched group of healthy volunteers served as the control group. DNA was isolated (Qiagen) (n=729 AZA;179 controls). Genotyping of NUDT15C415T(rs116855232;p.R139C) carried out employing Taq-man probes on Real-time PCR(Step one-Life tech). The association of presence of risk variant of NUDT15 with the development of leucopenia, other side effects and maximum tolerated dosage was evaluated. Results 711/729 patients were included in the analysis (18 inadequate DNA). (IDDF2018-ABS-0269 Table1) There was no significant differences in the frequency of C/C, C/T and T/T genotypes of NUDT15p.R139C between AZA group (82.28%, 15.75%–1.97%) and control group (88.27%,11.73%–0%). 79/711 patients developed leucopenia (26/585 C/C; 42/112C/T; 11/14 T/T). Development of leucopenia was significantly higher in C/T and T/T compared to C/C (OR 15.609; CI 9.198–26.490) (table 1). The sensitivity (67.08%) and specificity (88.45%) for predicting AZA-induced leucopenia. C/T group discontinued treatment significantly earlier than C/C genotype. There was no incidence of hepatitis/pancreatitis in C/T and T/T groups and no significant difference in the mean dose tolerated wild (C/C) vs risk variant (C/T,T/T) carriers(1.33 mg/kg vs 1.196 mg/kg;p=0.014). Conclusions NUDT15 risk genotype frequency is around 15% in Indian population and can predict the development of leucopenia. The results suggest thiopurines should be avoided in homozygous T/T and low dose for C/T heterozygous genotypes. This has important implications for clinical practice and is a step towards personalised management of IBD.