Thiopurine Methyltransferase Gene Polymorphisms in Chinese Patients with Inflammatory Bowel Disease

Abstract

Background: The thiopurine drugs azathioprine and 6-mercaptopurine are well established in the treatment of inflammatory bowel disease (IBD). However, great interpatient variability exists in the efficacy and toxicity of the drugs, and this results from thiopurine methyltransferase (TPMT) gene polymorphisms. The aim of this study was to identify the TPMT gene polymorphisms in Chinese IBD patients and to study the relationship between TPMT status and thiopurine-related toxicity in these patients. Materials and Methods: A total of 189 IBD patients, 87 with Crohn’s disease and 102 with ulcerative colitis, and 273 healthy controls were enrolled. All subjects were from the Han Chinese ethnic group. Polymorphisms in TPMT*2, *3A, *3B and *3C were analyzed using allele-specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. Direct sequencing was used to confirm the mutation results. Exons of the TPMT gene from patients who suffered from azathioprine-induced toxicity were amplified and sequenced to detect TPMT mutations. Results: No TPMT*2, *3A or *3B mutant alleles were detected. The allele frequency of TPMT*3C in the IBD group was 1.59%, which was similar to that of the healthy control group (1.59 vs. 1.47%, p = 1.000). Forty-three patients were treated with azathioprine therapy, 4 experienced myelotoxicity, and 1 experienced hepatotoxicity, so the incidence of drug toxicity was 11.7% (5/43). No TPMT*2, *3A, *3B or *3C polymorphisms were detected in these 5 patients. After directly sequencing the exons of the TPMT gene in these 5 patients, a synonymous single-nucleotide polymorphism (TPMT*1S), which does not alter the encoded amino acid, was found in 3 patients. Conclusion: TPMT*3C seemed to be a unique variant allele in this Han Chinese population. The overall frequencies of variant TPMT alleles in this population were lower than those in Caucasians, but thiopurinetoxicity in Han Chinese IBD patients is not low. Factors other than TPMT polymorphisms may be responsible for the development of toxicity.

The Same Intestinal Inflammatory Disease despite Different Genetic Risk Factors in the East and West?

“…As for the less frequent use of thiopurines, this may be restricted by limited experience in its use [35] and increased adverse effects that may be related to differences in thiopurine methyl-transferase (TPMT) polymorphisms in Asian patients [36]. Recently, a Korean group also discovered a single nucleotide polymorphism in NUDT15 , which may partially explain the higher incidence of thiopurine-induced leukopenia in Asians [37].…”

NUDT15 variant and thiopurine-induced leukopenia in Hong Kong

“…[9][10][11] Prospective TPMT genotyping can only identify a minor proportion of Asian patients who are at risk of thiopurine-induced myelosuppression. Moreover, the majority of Asian patients who are referred for TPMT genotyping after the occurrence of myelosuppression (called retrospective TPMT genotyping) do not carry any defective TPMT variant both in published studies 10,12,13 or in the experience of the authors' laboratory that has provided a TPMT genotyping service since 2013 (Table). There are clearly additional genetic and/or non-genetic factors that contribute to an increased risk of thiopurineinduced myelosuppression in Asians.…”

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

“…There is a poor correlation between weight‐based dosing of thiopurines and 6‐TGN and 6‐MMP levels 26. Previous studies have suggested that Asian patients do not tolerate full doses of thiopurines and have more toxicity 10, 18, 19, 20, 21. However, as mentioned above, these studies were based on estimation of TPMT genotype and activity rather than drug metabolites.…”

“…It is reported that the thiopurine metabolism differs in Asian patients who do not tolerate full dose of thiopurine 10, 18, 19, 20, 21. However, these studies were based on TPMT genotype and activity rather than metabolite estimation.…”