Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
Hum Mol Genet. 2010 Sep 15;19(18):3652-61. doi: 10.1093/hmg/ddq268. Epub 2010 Jun 29.
Several genome-wide association studies identified the chr15q25.1 region, which includes three nicotinic cholinergic receptor genes (CHRNA5-B4) and the cell proliferation gene (PSMA4), for its association with lung cancer risk in Caucasians. A haplotype and its tagging single nucleotide polymorphisms (SNPs) encompassing six genes from IREB2 to CHRNB4 were most strongly associated with lung cancer risk (OR = 1.3; P < 10(-20)). In order to narrow the region of association and identify potential causal variations, we performed a fine-mapping study using 77 SNPs in a 194 kb segment of the 15q25.1 region in a sample of 448 African-American lung cancer cases and 611 controls. Four regions, two SNPs and two distinct haplotypes from sliding window analyses, were associated with lung cancer. CHRNA5 rs17486278 G had OR = 1.28, 95% CI 1.07-1.54 and P = 0.008, whereas CHRNB4 rs7178270 G had OR = 0.78, 95% CI 0.66-0.94 and P = 0.008 for lung cancer risk. Lung cancer associations remained significant after pack-year adjustment. Rs7178270 decreased lung cancer risk in women but not in men; gender interaction P = 0.009. For two SNPs (rs7168796 A/G and rs7164594 A/G) upstream of PSMA4, lung cancer risks for people with haplotypes GG and AA were reduced compared with those with AG (OR = 0.56, 95% CI 0.38-0.82; P = 0.003 and OR = 0.73, 95% CI 0.59-0.90, P = 0.004, respectively). A four-SNP haplotype spanning CHRNA5 (rs11637635 C, rs17408276 T, rs16969968 G) and CHRNA3 (rs578776 G) was associated with increased lung cancer risk (P = 0.002). The identified regions contain SNPs predicted to affect gene regulation. There are multiple lung cancer risk loci in the 15q25.1 region in African-Americans.
几项全基因组关联研究确定了包含三个烟碱型乙酰胆碱受体基因（CHRNA5-B4）和细胞增殖基因（PSMA4）的 15q25.1 区域与白种人肺癌风险相关。一个单倍型及其包含从 IREB2 到 CHRNB4 的六个基因的标记单核苷酸多态性（SNP）与肺癌风险最强烈相关（OR=1.3；P<10(-20)）。为了缩小关联区域并确定潜在的因果变异，我们在一个包含 448 例非裔美国肺癌病例和 611 例对照的 15q25.1 区域 194kb 片段中的 77 个 SNP 中进行了精细映射研究。从滑动窗口分析中，有四个区域、两个 SNP 和两个不同的单倍型与肺癌相关。CHRNA5 rs17486278 G 的 OR=1.28，95%CI 1.07-1.54，P=0.008，而 CHRNB4 rs7178270 G 的 OR=0.78，95%CI 0.66-0.94，P=0.008，与肺癌风险相关。在调整吸烟量后，肺癌相关性仍然显著。rs7178270 降低了肺癌风险在女性中，但在男性中没有；性别交互作用 P=0.009。对于 PSMA4 上游的两个 SNP（rs7168796 A/G 和 rs7164594 A/G），与 AG 相比，具有 GG 和 AA 单倍型的人的肺癌风险降低（OR=0.56，95%CI 0.38-0.82；P=0.003 和 OR=0.73，95%CI 0.59-0.90，P=0.004，分别）。跨越 CHRNA5（rs11637635 C、rs17408276 T、rs16969968 G）和 CHRNA3（rs578776 G）的四个 SNP 单倍型与肺癌风险增加相关（P=0.002）。确定的区域包含预测影响基因调控的 SNP。在非裔美国人的 15q25.1 区域存在多个肺癌风险位点。
