NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease

Abstract

Thiopurine has been used to maintain remission and to reduce antidrug antibody formation in monoclonal antibody therapy in patients with inflammatory bowel disease (IBD). The use of thiopurine is limited by side effects such as leukopenia. Thiopurine S-methyltransferase (<i>TPMT</i>) variants are associated with thiopurine-induced leukopenia in Westerners, but the frequency of the risk alleles is low in Asians. Recently, a variant in the nudix hydrolase 15 (<i>NUDT15</i>) gene (R139C, c415C > T) was reported to be associated with early severe leukopenia in Asians. NUDT15 is an enzyme that converts 6-thio-(deoxy)guanosine triphosphate (6-T(d)GTP) to 6-thio-(deoxy)guanosine monophosphate (6-T(d)GMTP). The R139C variant impairs the stability of the protein and increases incorporation of 6-TGTP and 6-TdGTP into RNA and DNA, respectively, resulting in leukopenia. The frequency of C/C, C/T, and T/T are approximately 80%, 20%, and 1%, respectively in East Asians. Early leukopenia occurred in less than 3% of patients with C/C and in around 20% of those with C/T, whereas it occurred in almost all patients with T/T. Patients homozygous for this variant also develop severe hair loss. The measurement of <i>NUDT</i> R139C can increase the safety of thiopurine dramatically and is a successful example of personalized medicine in the field of IBD.

Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity

“…The frequency of NUDT15 polymorphism in this study was similar to that reported in previous studies in the East Asian population. 9,12,14 The development of AEs was more frequent in patients with C/T and T/T genotypes than in those with the C/C genotype. Patients with the T/T genotype should avoid thiopurine treatment because almost all of these patients experience severe AEs such as early severe leukopenia.…”

“…12 Therefore, genotyping of NUDT15 R139C is considered the best way to predict thiopurine-induced AEs in Asian patients. 11,14 Thiopurines should be contraindicated in patients with the T/T genotype because several studies have reported that almost all of these patients treated with thiopurines develop severe leukocytopenia and alopecia. 10,15 Patients with the C/T genotype also have a higher risk of dose-dependent AEs than patients with the C/C genotype.…”

Clinical characteristics of ulcerative colitis in elderly patients

“…Therefore, it is important to consider preventive strategies against adverse events while considering thiopurine therapy in elderly UC patients. NUDT15 gene variants should be routinely tested before initiating thiopurine therapy to avoid serious myelotoxicity from thiopurines 42 . Avoiding prolonged use of thiopurines and combination with anti‐tumor necrosis factor (TNF) agents may also reduce the risk of adverse events.…”

“…NUDT15 gene variants should be routinely tested before initiating thiopurine therapy to avoid serious myelotoxicity from thiopurines. 42 Avoiding prolonged use of thiopurines and combination with anti‐tumor necrosis factor (TNF) agents may also reduce the risk of adverse events.…”

TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India

“…Cytopenias, especially leucopenia, are recognized as a dose-dependent adverse effect of thiopurines. Cytopenias have been reported with a variable frequency in patients with thiopurine use and may result in significant treatment discontinuation and occasional morbidity [ 4 ]. Various enzymes like thiopurine S-methyltransferase (TPMT), xanthine oxidase and hypoxanthine phosphoribosyl transferase are enzymes involved in the metabolism of thiopurines [ 9 ].…”