结直肠癌风险新全基因组关联研究的荟萃分析。
Meta-analysis of new genome-wide association studies of colorectal cancer risk.
机构信息
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, USA.
出版信息
Hum Genet. 2012 Feb;131(2):217-34. doi: 10.1007/s00439-011-1055-0. Epub 2011 Jul 15.
Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.
在发达国家,结直肠癌是癌症死亡的第二大主要原因。全基因组关联研究(GWAS)已成功确定了结直肠癌的新易感性位点。为了跟进这些发现,并试图确定新的结直肠癌易感性位点,我们报告了先前未发表的主要关联的结直肠癌 GWAS 的结果(2906 例病例,3416 例对照)。具体来说,我们使用对数加性模型为每个研究计算了比值比和 95%置信区间。为了提高我们检测新的结直肠癌易感性位点的能力,我们对跨研究的结果进行了荟萃分析。我们使用十个独立的研究(8161 例病例和 9101 例对照)选择最具统计学意义的单核苷酸多态性(SNP)进行复制。我们再次使用荟萃分析来总结复制研究的结果,以及 GWAS 和复制研究的综合分析结果。我们测量了先前在结直肠癌易感性位点中确定的十个 SNP,并发现其中八个与结直肠癌相关(p 值范围为 0.02 至 1.8×10(-8))。当我们排除了先前对这些 SNP 发表过研究的研究时,在综合分析中,五个 SNP 在 p<0.05 时仍然显著。在经过多次测试调整后,在复制研究中没有新的易感性位点具有统计学意义,并且从 GWAS 和复制研究的综合分析来看,没有任何一个达到全基因组显著水平。我们在染色体位置 20p12 上的 BMP2 区域观察到第二个独立 SNP 的边缘显著证据(rs4813802;复制 p 值 0.03;综合 p 值 7.3×10(-5))。在 5p33.15 区域,包括 TERT-CLPTM1L 基因的编码区,GWAS 已经确定该区域与至少七种其他癌症的易感性有关,我们观察到与 rs2853668 的边缘显著关联(复制 p 值 0.03;综合 p 值 1.9×10(-4))。我们的研究表明,常见遗传变异对结直肠癌风险的贡献具有复杂性。