NUDT15

• Published in: Hong Kong medical journal = Xianggang yi xue za zhi 2016-04, Vol.22 (2), p.185
• Main Authors: Wong, Felix CK, Leung, Alex WK, Kwok, Jeffrey SS, Chan, Michael HM, Li, C K, Yuen, Y P
• Format: Article
• Language: chi ; eng
• Subjects: Apoptosis; Asian people; Consortia; Drug dosages; Genotype & phenotype; Inflammatory bowel disease; Laboratories; Leukemia; Leukopenia; Metabolism; Metabolites; Patients; White people
• ISSN: 1024-2708; 2226-8707
• DOI: 10.12809/hkmj154783

[...]6-TGNs exert their therapeutic effect by inducing apoptosis of T lymphocytes.1Myelosuppression, manifesting as a reduction in one or more of the haematopoietic lineages (most commonly leukopenia), is a serious adverse drug reaction related to the excessive generation of 6-TGNs.2 Thiopurine S-methyltransferase (TPMT) diverts 6-MP from the formation of 6-TGNs by converting 6-MP into inactive metabolites. [...]TPMT deficiency plays a causal role in the pathogenesis of thiopurine-induced leukopenia by shunting thiopurine metabolites towards the formation of excessive 6-TGNs. Prospective TPMTgenotyping has been recommended by the US Food and Drug Administration.4 5 In addition, guidelines on TPMT genotype[-]based dosage recommendations are currently available that include a reduced thiopurine starting dose or use of an alternative non-thiopurine treatment in individuals who carry defective TPMT allele(s).6 7 In Hong Kong, many patients are prescribed thiopurine without prospective TPMT genotyping, largely because of the low frequency of TPMTvariants in the Asian, including Chinese, population. The predominant TPMT variant in the Asian population is *3C (all other variants being exceedingly rare), with an allele frequency of 2.3%, in contrast to the higher allele frequency of TPMTvariants in the Caucasian population (5.3% for allTPMT variants detected in one study).8 Nevertheless, thiopurine-induced myelosuppression is more common in the Asian than Caucasian population.9 10 11Prospective TPMT genotyping can only identify a minor proportion of Asian patients who are at risk of thiopurine-induced myelosuppression. [...]the majority of Asian patients who are referred for TPMT genotyping after the occurrence of myelosuppression (called retrospective TPMTgenotyping) do not carry any defective TPMT variant both in published studies10 12 13 or in the experience of the authors' laboratory that has provided a TPMTgenotyping service since 2013 (Table). NUDT15 is a nudix hydrolase that degrades 8-oxo-dGTP and 8-oxo-dGDP in vitro, suggesting that it prevents misincorporation of 8-oxo-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGDP) into DNA in vivo.3 18 In-vitro studies showed that treatment with 6-MP resulted in a higher percentage of apoptosis and necrosis in cells transfected with the NUDT15R139C construct compared with cells with the wild-type construct.14 We performed NUDT15 R139C testing by polymerase chain reaction and bidirectional Sanger sequencing on all patien