Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study.
Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study.
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DOI：
10.1158/0008-5472.can-09-0680
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发表时间：
2009-08-15
期刊：
影响因子：
11.2
通讯作者：
Houlston RS
中科院分区：
文献类型：
--
作者：
Broderick P;Wang Y;Vijayakrishnan J;Matakidou A;Spitz MR;Eisen T;Amos CI;Houlston RS
为了探索常见变异对肺癌发生风险的影响，我们进行了一项两阶段全基因组关联（GWA）研究。在第一阶段，我们比较了1，952例病例和1，438例对照的511，919个标记单核苷酸多态性（tagSNP）的基因型;在第二阶段，在2，465例病例和3，005例对照中对30，568个SNP进行了基因分型。SNP选择基于来自肺癌的I期和另外两项GWA研究的最佳支持P值。在第1阶段和第2阶段的联合分析中，确定的最强关联由映射到15q25.1（rs 12914385; P = 3.19 × 10 - 16）、5p15.33（rs 4975616; P = 6.66 × 10 - 7）和6p21.33（rs3117582; P = 9.13 × 10 - 7）的SNP定义。15q25.1的变异，而不是5p15.33或6p21.33，与吸烟行为密切相关，风险等位基因与较高的消费量相关。在5p15.33的变异显示出显著影响肺癌组织学的诱导。来自四个系列的汇总数据提供了7，560例病例和8，205例对照的21，620种基因型。一项荟萃分析提供了更多的支持，即15q25.1（rs 8034191; P = 3.24 × 10−26），5p15.33（rs 4975616; P = 2.99 × 10−9）和6p21.33（rs3117582; P = 4.46 × 10−10）的变异影响肺癌风险。第二个最佳支持的关联出现在15q15.2（rs748404; P = 1.08 × 10−6）和10q23.31（rs 1926203; P = 1.28 × 10−6）。这些数据表明，很少有常见的变异占1%的超额家族风险，强调有必要有额外的大样本系列的基因发现。
To explore the impact of common variation on the risk of developing lung cancer we conducted a two-phase genome-wide association (GWA) study. In Phase 1, we compared the genotypes of 511,919 tagging single nucleotide polymorphisms (tagSNPs) in 1,952 cases and 1,438 controls; in Phase 2, 30,568 SNPs were genotyped in 2,465 cases and 3,005 controls. SNP selection was based on best supported P-values from Phase 1 and two other GWA studies of lung cancer. In the combined analysis of Phases 1 and 2, the strongest associations identified were defined by SNPs mapping to 15q25.1 (rs12914385; P = 3.19 × 10−16), 5p15.33 (rs4975616; P = 6.66 × 10−7), and 6p21.33 (rs3117582; P = 9.13 × 10−7). Variation at 15q25.1, but not 5p15.33 or 6p21.33, was strongly associated with smoking behaviour with risk alleles correlated to higher consumption. Variation at 5p15.33 was shown to significantly influence induction of lung cancer histology. Pooling data from the four series provided 21,620 genotypes for 7,560 cases and 8,205 controls. A meta-analysis provided increased support that variation at 15q25.1 (rs8034191; P = 3.24 × 10−26), 5p15.33 (rs4975616; P = 2.99 × 10−9), and 6p21.33 (rs3117582; P = 4.46 × 10−10) influences lung cancer risk. The next best-supported associations were attained at 15q15.2 (rs748404: P = 1.08 × 10−6) and 10q23.31 (rs1926203; P = 1.28 × 10−6). These data indicate few common variants account for 1% of the excess familial risk underscoring the necessity of having additional large sample series for gene discovery.