Genetic Variants on Chromosome 15q25 Associated with Lung Cancer Risk in Chinese Populations
Genetic Variants on Chromosome 15q25 Associated with Lung Cancer Risk in Chinese Populations
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15q25 染色体遗传变异与中国人群肺癌风险相关
DOI：
10.1158/0008-5472.can-09-0081
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发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Shen, Hongbing
中科院分区：
文献类型：
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作者：
Wu, Chen;Hu, Zhibin;Shen, Hongbing
最近的三项全基因组关联研究已经将高加索人肺癌易感基因定位于染色体15 q25。然而，报告的风险单核苷酸多态性（SNP）在亚洲人中非常罕见，反对任何这些致病变异。本研究旨在鉴定与中国人肺癌易感性相关的15 q25上的其他变异。在来自中国北方和南方的受试者中进行了两阶段病例对照研究。第一阶段包括576例病例和576例对照，使用单倍型标记SNP方法发现新的风险变异，然后在第二阶段复制这些变异，包括2，989例病例和2，880例对照。通过逻辑回归模型估计关联，并通过生化测定检查变体的功能。我们发现在白种人中报道的三个风险SNPs与中国人的肺癌风险无关。然而，我们发现了四个新的SNP，（rs 2036534 C>T、rs667282 C>T、rs 12910984 G>A和rs6495309 T>C）与显著增加的肺癌风险和吸烟行为相关，这些都在重复分析中得到证实[比值比（95%置信区间）在主导模型中：1.39（1.23-1.57; P = 2.3 x 10（-7））、1.52（1.35-1.71; P = 2.0 x 10（-12））、1.44（1.28-1.63; P = 2.7 x 10（-9））和1.43（1.27-1.61; P = 2.6 x 10（-9））]。我们将CHRNA 3启动子中的rs6495309 T>C变化表征为功能变体，因为它影响Oct-1结合能力，导致CHRNA 3表达增加。这些结果支持15 q25作为中国人肺癌的易感区域，但强调了不同种族人群之间遗传标记的差异。[Cancer Res 2009;69（12）：5065-72]
Recent three genome-wide association studies have mapped a lung cancer susceptibility locus to chromosome 15q25 in Caucasians. However, the reported risk single nucleotide polymorphisms (SNPs) are extremely rare in Asians, arguing against any of these being causative variants. This study sought to identify other variants on 15q25 associated with lung cancer susceptibility in Chinese. Two-stage case-control studies were conducted in subjects derived from both Northern and Southern China. The first-stage, consisting of 576 cases and 576 controls, was to discover novel risk variants using a haplotype-tagging SNP approach, and these variants were then replicated in the second-stage, consisting of 2,989 cases and 2,880 controls. Associations were estimated by logistic regression models, and function of the variants was examined by biochemical assays. We found that the three risk SNPs reported in Caucasians were not associated with lung cancer risk in Chinese. However, we identified four novel SNPs (rs2036534C>T, rs667282C>T, rs12910984G>A, and rs6495309T>C) that were associated with significantly increased lung cancer risk and smoking behavior, which were all confirmed in the replication analyses [odds-ratios (95% confidence intervals) in the dominant model: 1.39 (1.23-1.57; P = 2.3 x 10(-7)), 1.52 (1.35-1.71; P = 2.0 x 10(-12)), 1.44 (1.28-1.63; P = 2.7 x 10(-9)), and 1.43 (1.27-1.61; P = 2.6 x 10(-9)), respectively]. We characterized the rs6495309T>C change in the CHRNA3 promoter as a functional variant because it affected the Oct-1 binding ability, resulting in increased CHRNA3 expression. These results support 15q25 as a susceptibility region for lung cancer in Chinese but underscore the difference in genetic markers among different ethnic populations. [Cancer Res 2009;69(12):5065-72]