The Impact Of Genetic Polymorphisms On Toxicity And Efficacy Of Azathioprine In Patients With Inflammatory Bowel Diseases

Objective: To analyze the frequencies of TPMT*3C and NUDT15 R139 C in patients with inflammatory bowel disease(IBD),and to evaluate the impact of genetic polymorphisms on the toxicity and efficacy of azathioprine(AZA)in the treatment of IBD under traditional step-up dosing strategy.Methods: In the first part,358 IBD patients who were genotyped for TPMT*3C and NUDT15 R139 C at Renji Hospital from August 2016 to January 2018 were retrospectively identified.The frequencies of the two alleles were calculated and compared with each other.A total of 159 patients who started AZA therapy were subsequently included in the second part.The incidence of myelotoxicity and other adverse reactions were determined and correlated with genetic polymorphisms in the general population and different dose subgroups.In the third part,only 115 patients who had received AZA for more than 4 months and maintained clinical remission without steroids or biologics were eligible for efficacy evaluation.Time to relapse was compared between patients with different genotypes.Results:(1)The frequencies of TPMT AA and AG genotypes were 97.5% and 2.5%,respectively;The frequencies of NUDT15 CC,CT and TT genotypes were 77.4%,20.7 % and 2.0%,respectively;The allele frequency of NUDT15 R139 C was significantly higher than that of TPMT*3C(12.29% vs 1.25%;P< 0.001).(2)NUDT15 CC genotype was associated with AZA induced myelotoxicity(OR=3.08,P=0.01).At an initial dose of 25 mg/d,there was no significant difference in the incidence of myelotoxicity between the CT genotype and the CC genotype.However,when the dose was escalated to 50 mg/d,the occurrence of myelotoxicity in the heterozygotes was remarkably higher than the wild-genotypes.(40.0% vs 13.2%;P=0.001).Multivariate logistic regression revealed that patients with CT genotype had a 5-fold risk of developing myelotoxicity at a dose of 50 mg/d(P= 0.01)as compared with those with CC genotype.In addition to myelotoxicity,the CT genotype were more prone to alopecia than the wild-genotype(P= 0.042).There was no correlation between TPMT*3C and adverse reactions(P>0.05).(3)The time to relapse in patients with NUDT15 CT genotype and CC genotype were comparably the same(21 vs 25 months,P=0.86)on AZA monotherapy.However,the dose and weight adjusted dose of the CT genotype were significantly lower than those of the CC genotype [50.00 respectively(50.00-50.00)vs 75.00(50.00-75.00)mg/d,0.83(0.75-0.96)vs 1.04(0.89-1.33)mg/kg/d;P<0.001,P<0.001].Similar results were obtained in the subgroup analysis in patients with Crohn’s disease.Conclusions: NUDT15 R139 C is an important predictor of AZA related myelotoxicity and alopecia which is more prevalent than TPMT*3C in Chinese IBD patients.At a low dose of 50 mg/d,the risk of myelotoxicity in NUDT15 R139 C heterozygous patients remains high.However,AZA can be administered in NUDT15 R139 C heterozygotes at a lower dose without compromising efficacy in comparison with the wild-genotypes.