Gut Health Research Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Intern Med J. 2022 Nov;52(11):1971-1977. doi: 10.1111/imj.15746. Epub 2022 Jun 8.
Thiopurine-related adverse events such as leukopenia, liver dysfunction and pancreatitis are associated with variants in the NUDT15 gene. Loss-of-function (low or no enzyme activity) alleles are more common in Asian and Hispanic populations. The prevalence of these variants in the Australian inflammatory bowel disease (IBD) population has not yet been reported.
To evaluate the presence of NUDT15 loss-of-function alleles *2,*3,*9 in the Australian IBD population.
The NUDT15 screening cohort included 423 IBD patients from Brisbane, Australia. Study patients were recruited by: (i) retrospective review of clinical charts for thiopurine-related severe adverse events; (ii) pathology data (white blood cell (WBC) and neutrophil counts). NUDT15 genotyping was performed using polymerase chain reaction (PCR)-high-resolution melt (HRM), TaqMan genotyping and Sanger sequencing.
NUDT15 mutation R139C (allele *3) was identified in 8 of 423 (1.9%) IBD patients. Seven of eight patients were R139C heterozygous (C/T) and one patient was R139C homozygous (T/T). One of the C/T group and the T/T patient developed thiopurine-induced myelosuppression (TIM) within 60 days of dosing. One patient in the C/T group developed TIM after 60 days of thiopurine dosing. The remaining five patients in the C/T group did not show TIM; however, other thiopurine-related events could not be ruled out and therefore careful monitoring over a long period is recommended.
This is the first study to report the frequency of NUDT15 haplotypes *2,*3,*9 in an Australian IBD population. The most common variant detected was the R139C mutation. PCR and Sanger sequencing are efficient and cost-effective approaches for NUDT15 genotyping.
巯嘌呤相关不良反应，如白细胞减少症、肝功能障碍和胰腺炎，与 NUDT15 基因的变异有关。失活（低或无酶活性）等位基因在亚洲和西班牙裔人群中更为常见。这些变体在澳大利亚炎症性肠病（IBD）人群中的流行情况尚未报道。
评估 NUDT15 失活等位基因*2、*3、*9在澳大利亚 IBD 人群中的存在情况。
NUDT15 筛选队列包括来自澳大利亚布里斯班的 423 名 IBD 患者。研究患者通过以下方式招募：（i）回顾性审查与巯嘌呤相关严重不良反应相关的临床图表；（ii）病理数据（白细胞（WBC）和中性粒细胞计数）。使用聚合酶链反应（PCR）-高分辨率熔解（HRM）、TaqMan 基因分型和 Sanger 测序法进行 NUDT15 基因分型。
在 423 名 IBD 患者中发现 NUDT15 突变 R139C（等位基因*3）有 8 例（1.9%）。8 例患者中有 7 例为 R139C 杂合子（C/T），1 例为 R139C 纯合子（T/T）。C/T 组中的 1 例和 T/T 患者在开始巯嘌呤治疗后 60 天内出现了巯嘌呤诱导的骨髓抑制（TIM）。C/T 组中的 1 例患者在开始巯嘌呤治疗 60 天后出现 TIM。C/T 组中的其余 5 例患者未出现 TIM，但不能排除其他与巯嘌呤相关的事件，因此建议长期密切监测。
这是首次报道 NUDT15 单倍型*2、*3、*9在澳大利亚 IBD 人群中的频率。检测到的最常见变体是 R139C 突变。PCR 和 Sanger 测序是 NUDT15 基因分型的有效且具有成本效益的方法。
