miRNA processing gene polymorphisms, blood DNA methylation age and long-term ambient PM_2.5 exposure in elderly men

We tested whether genetic variation in miRNA processing genes modified the association of PM_2.5 with DNA methylation (DNAm) age.

We conducted a repeated measures study based on 552 participants from the Normative Aging Study with multiple visits between 2000 and 2011 (n = 940 visits). Address-level 1-year PM_2.5 exposures were estimated using the GEOS-chem model. DNAm-age and a panel of 14 SNPs in miRNA processing genes were measured from participant blood samples.

In fully adjusted linear mixed-effects models, having at least one copy of the minor rs4961280 [AGO2] allele was associated with a lower DNAm-age (β = -1.13; 95% CI: -2.26 to -0.002). However, the association of PM_2.5 with DNAm-age was significantly (P_interaction  = 0.01) weaker in homozygous carriers of the major rs4961280 [AGO2] allele (β = 0.38; 95% CI: -0.20 to 0.96) when compared with all other participants (β = 1.58; 95% CI: 0.76 to 2.39). Our results suggest that miRNA processing impacts DNAm-age relationships. Graphical abstract: miRNA processing AGO2 polymorphism (rs4961280) modifies the association of long-term ambient fine particle exposure with blood DNA methylation age [Formula: see text] The graph depicts lines from a fully adjusted linear regression model with fine particle exposure levels ranging from the tenth to the ninetieth percentile, all other continuous variables held constant at their means, and all other categorical variables held at their most frequent level.