Shi Jianxin, Marconett Crystal N, Duan Jubao, Hyland Paula L, Li Peng, Wang Zhaoming, Wheeler William, Zhou Beiyun, Campan Mihaela, Lee Diane S, Huang Jing, Zhou Weiyin, Triche Tim, Amundadottir Laufey, Warner Andrew, Hutchinson Amy, Chen Po-Han, Chung Brian S I, Pesatori Angela C, Consonni Dario, Bertazzi Pier Alberto, Bergen Andrew W, Freedman Mathew, Siegmund Kimberly D, Berman Benjamin P, Borok Zea, Chatterjee Nilanjan, Tucker Margaret A, Caporaso Neil E, Chanock Stephen J, Laird-Offringa Ite A, Landi Maria Teresa
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
1] Department of Surgery, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California 90089, USA [2] Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California 90089, USA.
Nat Commun. 2014 Feb 27;5:3365. doi: 10.1038/ncomms4365.
The genetic regulation of the human epigenome is not fully appreciated. Here we describe the effects of genetic variants on the DNA methylome in human lung based on methylation-quantitative trait loci (meQTL) analyses. We report 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude, including a regulatory hotspot. These findings are replicated in both breast and kidney tissues and show distinct patterns: cis-meQTLs mostly localize to CpG sites outside of genes, promoters and CpG islands (CGIs), while trans-meQTLs are over-represented in promoter CGIs. meQTL SNPs are enriched in CTCF-binding sites, DNaseI hypersensitivity regions and histone marks. Importantly, four of the five established lung cancer risk loci in European ancestry are cis-meQTLs and, in aggregate, cis-meQTLs are enriched for lung cancer risk in a genome-wide analysis of 11,587 subjects. Thus, inherited genetic variation may affect lung carcinogenesis by regulating the human methylome.
人类表观基因组的遗传调控尚未得到充分认识。在此，我们基于甲基化数量性状位点（meQTL）分析，描述了基因变异对人肺DNA甲基化组的影响。我们报告了34304个顺式和585个反式meQTL，这是一种具有惊人规模的遗传-表观遗传相互作用，包括一个调控热点。这些发现已在乳腺和肾脏组织中得到重复，并呈现出不同的模式：顺式meQTL大多定位于基因、启动子和CpG岛（CGI）之外的CpG位点，而反式meQTL在启动子CGI中过度富集。meQTL单核苷酸多态性（SNP）在CCCTC结合因子（CTCF）结合位点、脱氧核糖核酸酶I高敏区域和组蛋白标记中富集。重要的是，欧洲血统人群中已确定的五个肺癌风险位点中有四个是顺式meQTL，并且在对11587名受试者的全基因组分析中，顺式meQTL总体上在肺癌风险中富集。因此，遗传变异可能通过调控人类甲基化组影响肺癌发生。
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