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Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking

Epigenetics Unit, Department of Surgery and Cancer, Imperial College London, W12 0NN, UK.
Human Molecular Genetics (Impact Factor: 6.68). 11/2012; 22(5). DOI: 10.1093/hmg/dds488
Source: PubMed

ABSTRACT A single CpG site within F2RL3 was recently found to be hypomethylated in peripheral blood genomic DNA from smokers compared to 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 to former and non-smokers, including an intragenic region of the aryl hydrocarbon receptor repressor gene (AHRR; cg05575921, p=2.31x10(-15); effect size = 14%-17%), an intergenic CpG island on 2q37.1 (cg21566642, p=3.73x10(-13); effect size = 12%), and a further intergenic region at 6p21.33 (cg06126421, p=4.96x10(-11), effect size = 7%-8%). 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 to 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 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.

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