Modifying role of endothelial function gene variants on the association of long-term PM2.5 exposure with blood DNA methylation age: The VA normative aging study

Jamaji C. Nwanaji-Enwerem*, Marie Abele Bind, Lingzhen Dai, Youssef Oulhote, Elena Colicino, Qian Di, Allan C. Just, Lifang Hou, Pantel Vokonas, Brent A. Coull, Marc G. Weisskopf, Andrea A. Baccarelli, Joel D. Schwartz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Recent studies have reported robust associations of long-term PM2.5 exposure with DNAmethylation-based measures of aging;yet, themolecular implications of these relationships remain poorly understood. We evaluated if genetic variation in 3 biologicalpathways implicated in PM2.5-related disease-oxidative stress, endothelial function, andmetal processing-could modify theeffect of PM2.5 on DNAm-age, one prominent DNAmethylation-basedmeasure of biological age. This analysis was based on 552individuals from the Normative Aging Study with at least one visit between 2000 and 2011 (n=940 visits). A genetic-scoreapproach was used to calculate aging-risk variant scores for endothelial function, oxidative stress, andmetal processingpathways. One-year PM2.5 and PM2.5 component (sulfate and ammonium) levels at participants' addresses were estimated usingthe GEOS-chem transportmodel. Blood DNAm-age was calculated using CpG sites on the Illumina HumanMethylation450BeadChip. In fully-adjusted linearmixed-effects models, the effects of sulfate on DNAm-age (in years) were greater inindividuals with high aging-risk endothelial function variant scoreswhen comparedwith individuals with low aging-riskendothelial function variant scores (Pinteraction = 0.0007; bHigh = 1.09, 95% CIHigh: 0.70, 1.48; βLow = 0.40, 95% CILow: 0.14, 0.67).Similar trends were observed in fully adjustedmodels of ammonium and total PM2.5 alone. No effect modification was observedby oxidative stress and metal processing variant scores. Secondary analyses revealed significant associations of serumendothelialmarkers, intercellular adhesionmolecule-1 (β=0.01, 95% CI: 0.002, 0.012) and vascular cell adhesionmolecule-1(β=0.002, 95% CI: 0.0005, 0.0026), with DNAm-age. Our results add novel evidence that endothelial physiology may be importantto DNAm-age relationships, but further research is required to establish their generalizability.

Original languageEnglish (US)
Pages (from-to)116-126
Number of pages11
JournalToxicological Sciences
Issue number1
StatePublished - Jul 1 2017


  • DNA methylation age
  • Endothelial function
  • Particulate matter 2.5

ASJC Scopus subject areas

  • Toxicology


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