发现与膀胱癌风险相关的新型 N-乙酰基转移酶 2（NAT2）基因遗传变异。

Discovery of a novel genetic variant in the N-acetyltransferase2 (NAT2) gene that is associated with bladder cancer risk.

机构信息

Jordan University of Science and Technology, Faculty of Medicine, Department of Pharmacology, Irbid, Jordan.

Jordan University of Science and Technology, Faculty of Medicine, Department of Pharmacology, Irbid, Jordan; 2Royal Medical Services, Department of Clinical Pharmacy, Irbid, Jordan.

出版信息

Acta Biochim Pol. 2023 Aug 18;70(3):575-582. doi: 10.18388/abp.2020_6590.

DOI:10.18388/abp.2020_6590

PMID:37595067

Abstract

Smoking is a main risk factor for bladder cancer (BC). NAT2 is a drug-metabolizing enzyme that catalyses the detoxification of many xenobiotics and carcinogens. Single nucleotide polymorphism (SNP) in NAT2 results in different acetylation phenotypes (fast, intermediate or slow). Certain NAT2 SNPs were associated with BC and/or modified the association of BC with smoking. However, limited evidence is available among BC patients or smokers from Jordan. This study aimed to discover novel SNPs in NAT2 and to assess the association with BC. This was a case-control study among 120 BC patients and 120 controls. Amplification of a 446 bp fragment of NAT2 encoding the N-catalytic domain was conducted using a polymerase chain reaction. Gene sequencing was done using Sanger-based technology. A total of 40 SNPs were detected. Two variants were significantly associated with BC (p<0.05); namely a novel c.87G>A and the reported c.341T>C. Regarding c.87G>A, genotype distribution was significantly associated with BC and subgroup analysis confirmed that this was significant in both smokers (p=0.007) and non-smokers (p=0.001). Regression subgroup analysis suggested GA as a risk factor among smokers (AOR= 2.356). The frequencies of TC and CC genotypes of c.341T>C were significantly higher in BC (p<0.05). This was statistically significant among smokers only (p=0.044), upon subgroup analysis. Multivariate analysis showed that subjects with TC genotype are 6.15 more likely to develop BC and regression subgroup analysis revealed TC as a risk factor among smokers (AOR=5.47). This is the first study from Jordan to report the association of smoking and two NAT2 variants with BC. The data supports the use of GA and TC genotypes of the novel c.87G>A and the reported c.341T>C SNPs, respectively as potential biomarkers of BC, particularly among smokers. Future investigations with a larger population are required to support our findings.

摘要

吸烟是膀胱癌（BC）的主要危险因素。NAT2 是一种药物代谢酶，可催化许多外源化学物和致癌物的解毒。NAT2 中的单核苷酸多态性（SNP）导致不同的乙酰化表型（快、中或慢）。某些 NAT2 SNPs 与 BC 相关，或改变了 BC 与吸烟的关联。然而，在约旦的 BC 患者或吸烟者中，可用的证据有限。本研究旨在发现 NAT2 中的新 SNP，并评估其与 BC 的关联。这是一项在 120 例 BC 患者和 120 例对照者中进行的病例对照研究。使用聚合酶链反应扩增 NAT2 编码 N-催化结构域的 446 bp 片段。使用基于 Sanger 的技术进行基因测序。共检测到 40 个 SNP。两个变体与 BC 显著相关（p<0.05）；即一个新的 c.87G>A 和已报道的 c.341T>C。关于 c.87G>A，基因型分布与 BC 显著相关，亚组分析证实，这在吸烟者（p=0.007）和非吸烟者（p=0.001）中均有统计学意义。回归亚组分析表明，GA 是吸烟者的危险因素（AOR=2.356）。c.341T>C 的 TC 和 CC 基因型在 BC 中的频率显著升高（p<0.05）。在吸烟者中，这具有统计学意义（p=0.044），经亚组分析。多变量分析表明，TC 基因型的受试者发生 BC 的可能性增加 6.15 倍，回归亚组分析表明，TC 是吸烟者的危险因素（AOR=5.47）。这是约旦首例报告吸烟和 NAT2 两种变体与 BC 相关的研究。数据支持使用新型 c.87G>A 的 GA 和 TC 基因型以及已报道的 c.341T>C SNP 分别作为 BC 的潜在生物标志物，特别是在吸烟者中。需要进行更大人群的未来研究来支持我们的发现。