NUDT15 Polymorphism Confer Increased Susceptibility to Thiopurine-Induced Leukopenia in Patients With Autoimmune Hepatitis and Related Cirrhosis

Abstract

The aim of this study was to investigate the influence of NUDT15 R139C and thiopurine S-methyltransferase ( TPMT ) on azathioprine (AZA) induced leukopenia in patients with autoimmune hepatitis (AIH) and related cirrhosis. A total of 149 Chinese AIH patients with a history of AZA treatment were retrospectively evaluated. The clinical and epidemiological characteristics of the patients were obtained from an electronic database and reviewed. NUDT15 (rs116855232) and TPMT ∗ 3C (rs1142345) SNPs were genotyped using a PCR method. Twelve patients developed leukopenia, and this adverse drug reaction was significantly associated with the T risk allele in NUDT15 [ P < 0.00001, odds ratio = 20.41; 95% confidence interval (CI) (7.84, 53.13)], with the sensitivity and specificity of 91.67 and 89.05%, respectively. The median maintenance dosages for patients with the rs116855232 CC and CT genotypes were 1.23 (0.95, 1.53) mg ⋅ kg −1 ⋅ d −1 and 0.96 (0.83, 1.19) mg ⋅ kg −1 ⋅ d −1 , respectively ( P = 0.028). In contrast, no significant association was observed for TPMT ∗ 3C genotypes. Notably, subgroup analysis of the 13 patients with leukopenia before therapy, these white blood cell (WBC) counts did not show further reduction after AZA treatment and maintenance dosage was 1.13 (0.94, 1.60) mg ⋅ kg −1 ⋅ d −1 . Therefore, NUDT15 polymorphism is significantly associated with thiopurine-induced leukopenia in Chinese patients with AIH and related cirrhosis. Adjusting the AZA dosage should be considered in patients according to the NUDT15 R139C genotypes.

Association of Genetic Variants in TPMT, ITPA,&nbsp;NUDT15&nbsp;With&nbsp;Azathioprine-Induced Myelosuppression in Southwest China Patients With Autoimmune Hepatitis

“…29 The frequency we observed in this study was 12.4%, which is the same as the frequency of 9.4% in AIH patients reported by Xiaoli Fan et al. 19 Recent studies have found NUDT15 c.415C > T variants were associated with thiopurine-induced leukopenia, particularly in Asian populations. 26,30−32 In 2014, Yang et al 11 revealed for the rst time that NUDT15 c.415C > T allelic mutation is signi cantly associated with AZA-induced leukopenia in Korean IBD patients (P = 5.58 × 10 − 43 , OR = 8.61).…”

“…Subsequently, it was also con rmed in Japanese IBD patients that NUDT15 c.415C > T allele mutation is closely related to AZA-induced early leukopenia 13 (P = 1.92 × 10 − 16, OR = 28.4). The studies by Xiang Fei et al 29 and Xiaoli Fan et al 19 on Chinese autoimmune diseases and AIH patients also showed that NUDT15 c.415C > T SNP is signi cantly related to AZA-induced early leukopenia (P = 1.79 × 10 − 7 ; OR = 7.59 and P < 0.00001; OR = 20.41, respectively). Our result was concordant with previous studies, which showed NUDT15 c.415C > T allelic mutation was associated with early leukopenia (P = 8.26 × 10 − 7 ; OR = 7.5).…”

“…In the research of Asada et al 12 and Xiang Fei et al 29 , there was no statistically signi cant concentration difference observed between different NUDT15c.415C > T genotypes. However, Xiaoli Fan et al 19 reported that the 6-TGN concentration in CT genotype patients in NUDT15c.415C > T variants was signi cantly higher than in CC wild-type patients. The above studies have shown no signi cant difference in the concentration of 6-TNG between patients with or without leukopenia.…”

“…However, only two related reports have been found for AIH patients, including a case report. 18,19 There has not been a comprehensive assessment of the relationship between genetic variants of TPMT*3C T > C, ITPA 94C > A, NUDT15 c.415C > T and AZA toxicity in southwest China AIH patients.…”

Methylprednisolone Decreases Mitochondria-Mediated Apoptosis and Autophagy Dysfunction in Hepatocytes of Experimental Autoimmune Hepatitis Model via the Akt/mTOR Signaling

“…Aberrant autoimmunity is thought to induce an interaction between genetic susceptibility and unknown environmental triggers to cause persistent hepatocyte damage. Precision medicine for AIH, including diagnosis, medicinal therapy, and drug monitoring, is a novel therapeutic pattern distinct from evidence-based medicine that aims to develop a personalized treatment strategy (Bossen et al, 2018; Chen et al, 2019; Fan et al, 2019). However, ∼20% of AIH patients exhibit a poor response to standard treatment with glucocorticoids alone or in combination with azathioprine, and the number of effective second-line therapeutic options for AIH is limited (2015; Cropley and Weltman, 2017; Shen et al, 2018).…”