Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking
A single cytosine–guanine 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 x 10–15; effect size = 14–17%), an intergenic CpG island on 2q37.1 (cg21566642, P = 3.73 x 10–13; effect size = 12%) and a further intergenic region at 6p21.33 (cg06126421, P = 4.96 x 10–11, 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 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.
Natalie S. Shenker; Silvia Polidoro; Karin van Veldhoven; Carlotta Sacerdote; Fulvio Ricceri; Mark A. Birrell; Maria G. Belvisi; Robert Brown; Paolo Vineis; James M. Flanagan
B lymphocytes are often essential to successfully control invading pathogens and play a primary role in the protection afforded by successful vaccines through the production of specific antibodies. However, recent studies have highlighted the complex roles of B cells in infectious diseases, ... mehr
Over the last decade it has become evident that in addition to producing antibody, B cells activate the immune system by producing cytokines and via antigen presentation. In addition, B cells also exhibit immunosuppressive functions via diverse regulatory mechanisms. This subset of B cells, ... mehr
Advances in understanding of the immune microenvironment have highlighted the role of immunosuppressive T cell, myeloid, dendritic and monocytic sub-populations in inhibition of the anti-tumor immune response. The role of B cells in modulating the immune response to solid tumors as well as ... mehr