Comparison of TPMT and NUDT15 polymorphisms in Chinese patients with inflammatory bowel disease

Abstract

AIMTo observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine (AZA)-induced leukopenia in inflammatory bowel disease (IBD).METHODSThis study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced leukopenia.RESULTSThere were 219 patients with IBD (160 men and 59 women), including 39 who were confirmed with ulcerative colitis (UC), 176 with Crohn’s disease (CD) and 4 with undetermined IBD (UIBD). There were 44 patients (20.1%) with mutant genotype of NUDT15 (C/T); among them, 16 received AZA, and 8 (50%) developed leukopenia. There were 175 patients (79.7%) with wild genotype of NUDT15 (C/C); among them, 64 received AZA, and 11 (17.2%) developed leukopenia. A significant difference was found between NUDT15 C/T and its wild-type C/C (P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G (1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients (98.6%) were found to bear the wild genotype of TPMT (A/A); among them, 79 patients received AZA, and 18 (22.8%) developed leukopenia, and there was no significant difference from those with A/G (P = 0.071). The frequency of TPMT mutation was 1.4%, and NUDT15 mutation rate was significantly higher and reached 20.1% (P = 0.000). Therefore, NUDT15 gene polymorphism was obviously a better biomarker than TPMT gene polymorphism in the prediction of AZA-induced leukopenia.CONCLUSIONMutation rate of NUDT15 in Chinese IBD patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA-induced leukopenia than TPMT polymorphism.

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

“…Detailed information of 19 studies evaluating the effect of concomitant treatment agents on the development of TIL can be found in Table S4 …”

“…Six studies showed no effect of concomitant corticosteroid use on TIL development . One Chinese cohort study showed that patients receiving concomitant corticosteroids had a significant lower risk to develop TIL (OR 0.20 (95% CI 0.05‐0.80)) …”

“…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). …”

“…Thirteen studies were identified that evaluated NUDT15 variants as risk factors for TIL in IBD patients, one also described the association of NUDT15 activity and TIL (Table S3). The majority of studies were performed in East‐Asian cohorts, one study included only patients of European ancestry . Studied NUDT15 variants were NUDT15 R139C (rs116855232) in 13 studies, NUDT15 c.36_37ins/delGGAGTC (rs746071566) in six studies and c.52G > A (rs186364861) in four studies.…”

“…In a multivariable regression analysis including 6‐TGN and 6‐MMP metabolite threshold parameters, thiopurine type and concomitant anti‐TNF treatment, a fivefold higher risk for TIL in patients receiving concomitant anti‐TNF was demonstrated . No effect of anti‐TNF co‐administration was found in five other studies, of which one did a separate analysis for early TIL . No association of concomitant anti‐TNF use and early TIL was found in a Japanese cohort after correction for male gender, age, AZA dose, and NUDT15 R139C risk allele counts .…”