Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking
Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking
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DOI：
10.1093/hmg/dds488
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发表时间：
2013-03-01
影响因子：
3.5
通讯作者：
Flanagan, James M.
中科院分区：
文献类型：
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作者：
Shenker, Natalie S.;Polidoro, Silvia;Flanagan, James M.
最近发现，与吸烟者和非吸烟者相比，吸烟者外周血基因组DNA中凝血因子II（凝血酶）受体样3（F2 RL 3）内的单个胞嘧啶鸟嘌呤二核苷酸（CpG）位点低甲基化。我们使用Illumina 450 K甲基化Beadchip在前瞻性健康队列中进行了两项表观全基因组关联研究（EWAS）。这两个群体由配对的健康个体组成（n = 374），其中一半人发展为乳腺癌或结肠癌。研究人员分析了甲基化与吸烟状况以及癌症风险之间的关系。除了F2 RL 3中的相同基因座，我们报告了吸烟者与前吸烟者和非吸烟者相比的几个低甲基化基因座，包括芳烃受体阻遏基因的基因内区域（AHRR; cg 05575921，P 2.31 10（15）;效应量1417），2q37.1上的基因间CpG岛（cg 21566642，P 3.73 10（13）;效应量12）和6p21.33处的另一基因间区域（cg 06126421，P 4.96 10（11），效应量78）。亚硫酸氢盐焦磷酸测序验证了6个基因座在进一步独立的健康个体人群（n 180）。与非吸烟者相比，当前吸烟者肺组织中AHRR的甲基化水平也显著降低（P 0.001），表达增加（P 0.0047）。这在烟雾暴露的小鼠模型中得到了进一步验证。我们观察到2q37.1位点与乳腺癌风险相关（P 0.003，经吸烟状态校正），但与吸烟相关的其他位点无关。这些数据表明，吸烟对肺组织中的表观基因组有直接影响，这在外周血DNA中也是可检测的，并可能导致癌症风险。
A single cytosineguanine dinucleotide (CpG) site within coagulation factor II (thrombin) receptor-like 3 (F2RL3) was recently found to be hypomethylated in peripheral blood genomic DNA from smokers compared with former and non-smokers. We performed two epigenome-wide association studies (EWAS) nested in a prospective healthy cohort using the Illumina 450K Methylation Beadchip. The two populations consisted of matched pairs of healthy individuals (n 374), of which half went on to develop breast or colon cancer. The association was analysed between methylation and smoking status, as well as cancer risk. In addition to the same locus in F2RL3, we report several loci that are hypomethylated in smokers compared with former and non-smokers, including an intragenic region of the aryl hydrocarbon receptor repressor gene (AHRR; cg05575921, P 2.31 10(15); effect size 1417), an intergenic CpG island on 2q37.1 (cg21566642, P 3.73 10(13); effect size 12) and a further intergenic region at 6p21.33 (cg06126421, P 4.96 10(11), effect size 78). Bisulphite pyrosequencing validated six loci in a further independent population of healthy individuals (n 180). Methylation levels in AHRR were also significantly decreased (P 0.001) and expression increased (P 0.0047) in the lung tissue of current smokers compared with non-smokers. This was further validated in a mouse model of smoke exposure. We observed an association with breast cancer risk for the 2q37.1 locus (P 0.003, adjusted for the smoking status), but not for the other loci associated with smoking. These data show that smoking has a direct effect on the epigenome in lung tissue, which is also detectable in peripheral blood DNA and may contribute to cancer risk.