Epigenomic profiling of isolated blood cell types reveals highly specific B cell smoking signatures and links to disease risk

Xuting Wang; Michelle R Campbell; Hye-Youn Cho; Gary S Pittman; Suzanne N Martos; Douglas A Bell

doi:10.1186/s13148-023-01507-8

Epigenomic profiling of isolated blood cell types reveals highly specific B cell smoking signatures and links to disease risk

Clin Epigenetics. 2023 May 25;15(1):90. doi: 10.1186/s13148-023-01507-8.

Authors

Xuting Wang¹, Michelle R Campbell², Hye-Youn Cho², Gary S Pittman², Suzanne N Martos², Douglas A Bell³

Affiliations

¹ Environmental Epigenomics and Disease Group, Immunity, Inflammation and Disease Laboratory, Intramural Research Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA. wang21@niehs.nih.gov.
² Environmental Epigenomics and Disease Group, Immunity, Inflammation and Disease Laboratory, Intramural Research Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
³ Environmental Epigenomics and Disease Group, Immunity, Inflammation and Disease Laboratory, Intramural Research Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA. bell1@niehs.nih.gov.

Abstract

Background: Tobacco smoking alters the DNA methylation profiles of immune cells which may underpin some of the pathogenesis of smoking-associated diseases. To link smoking-driven epigenetic effects in specific immune cell types with disease risk, we isolated six leukocyte subtypes, CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells, from whole blood of 67 healthy adult smokers and 74 nonsmokers for epigenome-wide association study (EWAS) using Illumina 450k and EPIC methylation arrays.

Results: Numbers of smoking-associated differentially methylated sites (smCpGs) at genome-wide significance (p < 1.2 × 10^-7) varied widely across cell types, from 5 smCpGs in CD8+ T cells to 111 smCpGs in CD19+ B cells. We found unique smoking effects in each cell type, some of which were not apparent in whole blood. Methylation-based deconvolution to estimate B cell subtypes revealed that smokers had 7.2% (p = 0.033) less naïve B cells. Adjusting for naïve and memory B cell proportions in EWAS and RNA-seq allowed the identification of genes enriched for B cell activation-related cytokine signaling pathways, Th1/Th2 responses, and hematopoietic cancers. Integrating with large-scale public datasets, 62 smCpGs were among CpGs associated with health-relevant EWASs. Furthermore, 74 smCpGs had reproducible methylation quantitative trait loci single nucleotide polymorphisms (SNPs) that were in complete linkage disequilibrium with genome-wide association study SNPs, associating with lung function, disease risks, and other traits.

Conclusions: We observed blood cell-type-specific smCpGs, a naïve-to-memory shift among B cells, and by integrating genome-wide datasets, we identified their potential links to disease risks and health traits.

Keywords: Blood cell types; DNA methylation; Epigenome-wide association study; Genetic variation; Memory B cell; Tobacco smoking.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Adult
CpG Islands
DNA Methylation*
Epigenesis, Genetic
Epigenomics
Genome-Wide Association Study
Humans
Leukocytes
Smoking* / adverse effects
Smoking* / genetics
Tobacco Smoking

Grants and funding

Z01 ES100475/ImNIH/Intramural NIH HHS/United States