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This study used a large-scale epigenome-wide association study (EWAS) with a novel methylation array (Illumina MSA) to identify 152 DNA methylation changes in blood associated with tobacco smoking across a multiethnic U.S. cohort of 887 individuals, with 91 of these findings replicated in an independent sample of 2,190 participants. A particularly notable discovery was a dense cluster of 12 differentially methylated positions within a 1117 bp region of ECEL1P1, representing the most persistent smoking-associated epigenetic signal detected to date, remaining present even in former smokers who had quit decades earlier. The study further found that smoking-related DNA methylation changes are concentrated in hematopoietic stem and progenitor cells, suggesting these cells retain a long-term epigenetic record of smoking exposure while myeloid cells exhibit shorter-term, more transient changes.
Why it matters
The identification of persistent epigenetic marks in hematopoietic stem cells could help explain why former smokers remain at elevated risk for smoking-related diseases long after cessation, and these findings may eventually contribute to biomarker development for assessing cumulative smoking exposure and associated health risks.
⚠️ Preprint – Noch nicht peer-reviewed
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Tobacco smoking induces DNA methylation (DNAm) changes in blood and other tissues, which may influence chronic health outcomes. However, the breadth of smoking-related DNAm changes remains unmapped, offering a space for employing novel technologies. To expand our understanding of smoking impacts on DNAm, we conducted an epigenome-wide association study (EWAS) comparing ever smokers to never smokers, using blood from a multiethnic U.S. study population (n=887). We employed the newly developed Illumina Methylation Screening Array (MSA) covering 269,094 unique sites, including 123,776 CpGs not assayed in previous EWAS. Trans-ethnic meta-analysis identified 152 differentially methylated positions (DMPs) associated with ever-smoking status (n=764); European-specific analysis yielded 129 DMPs (n=674), including 106 overlapping with trans-ethnic analysis. A separate, large-scale replication EWAS (n=2,190) confirmed 91 trans-ethnic and 77 European-specific DMPs. Among our findings, we identified 61 DMPs at CpGs novel to the MSA platform, including near both new and known smoking-associated genes. Most notably, we uncovered a dense cluster of 12 DMPs within a 1117 bp region of ECEL1P1, forming the most long-lasting, persistent smoking-associated DMR ever detected, even among former smokers who quit decades prior. We also detected new signals at AHRR, a well-known locus for smoking-related DNAm changes. eFORGE analysis revealed that detected smoking-associated DNAm changes are predominantly located in hematopoietic stem and progenitor cell (HSPC) DNase I hotspots, aligning with gene set enrichment analyses that highlighted pathways related to hematopoietic stem cell differentiation. Our findings suggest that HSPCs serve as a reservoir for an epigenetic memory of smoking. Additionally, we observed short-term cell-specific smoking-associated DNAm changes in myeloid cells. Our results demonstrate the utility of the MSA in expanding our knowledge of both transient and persistent environmental exposure-associated DNAm changes.
Source: Smoking drives an epigenetic memory of aberrant hematopoiesis