Shah Swarup A V, Paradkar Minal, Desai Devendra, Ashavaid Tester F
Department of Research Laboratories, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India.
Department of Gastroenterology, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India.
J Gastroenterol Hepatol. 2017 Mar;32(3):620-624. doi: 10.1111/jgh.13494.
Interindividual variation seen in the thiopurine metabolism is attributed to the genetic variant in thiopurine methyltransferase (TPMT) gene leading to myelosuppression. In Asians, the thiopurine-induced toxicity is not completely explained by TPMT variants. Literature indicates that a newer genetic variant in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene is associated with thiopurine intolerance. We aimed to determine the risk allele frequency of NUDT15 genetic variant and its association with thiopurine-induced toxicity in Indian patients.
In this pilot study, 69 patients on thiopurine therapy were analyzed. The frequencies of thiopurine-induced leukopenia were recorded. NUDT15 (C415T) and TPMT (*2, *3A, *3B, and *3C) genotyping was performed using amplification refractory mutation system-polymerase chain reaction and restriction fragment length polymorphism technique. Results were validated by DNA sequencing.
The NUDT15 CC, CT, and TT genotypes were found to be 86.9%, 11.5%, and 1.5%, respectively, whereas TPMT genetic variants were absent. Of 60 patients without NUDT15 variant, none developed leukopenia, whereas of nine patients with NUDT15 variant, six developed leukopenia (P-value < 0.0001). The mean thiopurine dose of 1.01 and 0.73 mg/kg/day for patients with wild and mutant NUDT15 alleles, respectively, was statistically significant (P < 0.01). The sensitivity and specificity for NUDT15 variant were 100% and 95.2%, respectively.
The NUDT15 risk allele frequency was 7.2%. There are 6/69 (8.7%) patients who developed leukopenia and harbored NUDT15 variant, thus showing a strong association for thiopurine-induced toxicity. Hence, NUDT15 genotyping may be considered before thiopurine therapy in Indian patients.
硫嘌呤代谢中个体间的差异归因于硫嘌呤甲基转移酶（TPMT）基因的遗传变异，该变异会导致骨髓抑制。在亚洲人中，硫嘌呤诱导的毒性不能完全由TPMT变异来解释。文献表明，核苷二磷酸连接部分X型基序15（NUDT15）基因中的一种新的遗传变异与硫嘌呤不耐受有关。我们旨在确定印度患者中NUDT15基因变异的风险等位基因频率及其与硫嘌呤诱导毒性的关联。
在这项初步研究中，对69例接受硫嘌呤治疗的患者进行了分析。记录硫嘌呤诱导的白细胞减少的发生率。使用扩增阻滞突变系统-聚合酶链反应和限制性片段长度多态性技术进行NUDT15（C415T）和TPMT（*2、*3A、3B和3C）基因分型。结果通过DNA测序进行验证。
发现NUDT15的CC、CT和TT基因型分别为86.9%、11.5%和1.5%，而未发现TPMT基因变异。在60例无NUDT15变异的患者中，无人发生白细胞减少，而在9例有NUDT15变异的患者中，6例发生了白细胞减少（P值<0.0001）。野生型和突变型NUDT15等位基因患者的硫嘌呤平均剂量分别为1.01和0.73毫克/千克/天，差异具有统计学意义（P<0.01）。NUDT15变异的敏感性和特异性分别为100%和95.2%。
NUDT15风险等位基因频率为7.2%。有6/69（8.7%）例发生白细胞减少的患者携带NUDT15变异，因此显示出与硫嘌呤诱导的毒性有很强的关联。因此，在印度患者接受硫嘌呤治疗前可考虑进行NUDT15基因分型。
