Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, MD, USA.
Pharmacogenet Genomics. 2011 Apr;21(4):231-6. doi: 10.1097/FPC.0b013e32833e1b54.
The arylamine N-acetyltransferase 2 (NAT2) slow acetylation phenotype is an established risk factor for urinary bladder cancer. We reported earlier on this risk association using NAT2 phenotypic categories inferred from NAT2 haplotypes based on seven single nucleotide polymorphisms (SNPs) in a study in Spain. In a subsequent genome-wide scan, we have identified a single common tag SNP (rs1495741) located in the 3' end of NAT2 that is also associated with bladder cancer risk. The aim of this report is to evaluate the agreement between the common tag SNP and the 7-SNP NAT2 inferred phenotype. The agreement between the 7-SNP NAT2 inferred phenotype and the tag SNP, rs1495741, was initially assessed in 2174 individuals from the Spanish Bladder Cancer Study (SBCS), and confirmed in a subset of individuals from the Main and Vermont component the New England Bladder Cancer Study (NEBCS). We also investigated the association of rs1495741 genotypes with NAT2 catalytic activity in cryopreserved hepatocytes from 154 individuals of European background. We observed very strong agreement between rs1495741 and the 7-SNP inferred NAT2 phenotype: sensitivity and specificity for the NAT2 slow phenotype was 99 and 95%, respectively. Our findings were replicated in an independent population from the NEBCS. Estimates for the association between NAT2 slow phenotype and bladder cancer risk in the SBCS and its interaction with cigarette smoking were comparable for the 7-SNP inferred NAT2 phenotype and rs1495741. In addition, rs1495741 genotypes were strongly related to NAT2 activity measured in hepatocytes (P<0.0001). A novel NAT2 tag SNP (rs1495741) predicts with high accuracy the 7-SNP inferred NAT2 phenotype, and thus can be used as a sole marker in pharmacogenetic or epidemiological studies of populations of European background. These findings illustrate the utility of tag SNPs, often used in genome-wide association studies (GWAS), to identify novel phenotypic markers. Further studies are required to determine the functional implications of rs1495741 and the structure and evolution of the haplotype on which it resides.
芳香胺 N-乙酰基转移酶 2（NAT2）的缓慢乙酰化表型是膀胱癌的一个既定风险因素。我们之前曾使用基于七个单核苷酸多态性（SNP）的 NAT2 单倍型推断的 NAT2 表型类别报告过这种风险关联，该研究在西班牙进行。在随后的全基因组扫描中，我们已经确定了一个位于 NAT2 3'端的单个常见标记 SNP（rs1495741），它也与膀胱癌风险相关。本报告的目的是评估常见标记 SNP 与 7-SNP NAT2 推断表型之间的一致性。在西班牙膀胱癌研究（SBCS）的 2174 名个体中，首先评估了 7-SNP NAT2 推断表型与常见标记 SNP（rs1495741）之间的一致性，并在新英格兰膀胱癌研究（NEBCS）的主要和佛蒙特州部分个体中进行了确认。我们还研究了 rs1495741 基因型与来自 154 名欧洲背景个体的冷冻保存肝细胞中 NAT2 催化活性的关系。我们观察到 rs1495741 与 7-SNP 推断的 NAT2 表型之间非常强的一致性：NAT2 慢表型的敏感性和特异性分别为 99%和 95%。我们的发现在来自 NEBCS 的独立人群中得到了复制。在 SBCS 中，NAT2 慢表型与膀胱癌风险之间的关联及其与吸烟的相互作用的估计值，对于 7-SNP 推断的 NAT2 表型和 rs1495741 是可比的。此外，rs1495741 基因型与肝细胞中测量的 NAT2 活性密切相关（P<0.0001）。一种新的 NAT2 标记 SNP（rs1495741）可以非常准确地预测 7-SNP 推断的 NAT2 表型，因此可以作为欧洲背景人群的遗传药理学或流行病学研究中的单一标记物使用。这些发现说明了标记 SNP 的实用性，标记 SNP 通常用于全基因组关联研究（GWAS），以确定新的表型标记。需要进一步的研究来确定 rs1495741 的功能意义以及它所在的单倍型的结构和进化。
