Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte SubtypesReportar como inadecuado

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Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking–associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing RRBS to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking p <1.2x10-7, Bonferroni correction. Several CpGs MTSS1, NKX6-2, BTG2 were associated with smoking duration among heavy smokers >22 cigarettes-day, n = 86 which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR cg05575921, ALPPL2 cg21566642, GFI1 cg09935388, IER3 cg06126421 and F2RL3 cg03636183 showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes>> B cells. In contrast GPR15 cg19859270 was highly significant in T and B cells and ITGAL cg09099830 significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions DMRs with RRBS in 6 cell types, we confirmed cell-type specificity in the context of DMRs. We identified new CpGs associated with current smoking, pack-years, duration, and revealed unique profiles of smoking-associated DNA methylation and gene expression among immune cell types, providing potential clues to hematopoietic lineage-specific effects in disease etiology.

Autor: Dan Su , Xuting Wang , Michelle R. Campbell, Devin K. Porter, Gary S. Pittman, Brian D. Bennett, Ma Wan, Neal A. Englert, Christo

Fuente: http://plos.srce.hr/


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