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2624223 
Journal Article 
Abstract 
Changes in endothelial function, PM2.5 exposures, and interactions with SNPs in microRNA processing genes: the VA Normative Aging Study 
Wilker, E; Ackerman-Alexeeff, S; Vokonas, P; Baccarelli, A; Schwartz, J 
2010 
Yes 
American Journal of Respiratory and Critical Care Medicine
ISSN: 1073-449X
EISSN: 1535-4970 
181 
A4005 
English 
WOS:000208771003350 
is part of a larger document 3452678 Proceedings of the American Thoracic Society 2010 International Conference, May 14-19, 2010, New Orleans
Background: Ambient exposure to particulate air pollution has been associated with cardiovascular effects including increases in inflammation and endothelial dysfunction. MicroRNAs (MiRNAs) are small non-coding RNAs that repress or inhibit gene expression by targeting messenger RNA (mRNA). Specific miRNAs have been associated with cardiovascular disease, but it is unclear whether miRNA biogenesis and processing influences cardiovascular susceptibility to particulate matter. We investigated the associations between particulate matter<2.5 µg in diameter (PM2.5) and two markers of endothelial function: intercellular adhesion molecule (ICAM-1) and vascular cellular adhesion molecule (VCAM-1). Additionally, we tested interactions between PM2.5 and 14 functional single nucleotide polymorphisms (SNPs) in 4 miRNA processing genes: GEMIN3, GEMIN4, Dicer and Drosha.

Methods: Serum ICAM-1 and VCAM-1 were measured at study visits every 3-5 years. Continuous PM2.5 was measured 1 km from the study site and we used a 2-day moving average for all analyses. We investigated the main effects of PM2.5 and SNP-by-PM2.5 interactions using linear mixed-effects models with subject-specific intercepts under dominant models of inheritance for SNPs. Mixed-effect models were adjusted for potential confounders including clinical and lifestyle characteristics, time trends, and meteorological factors.

Results: Data were available on 719 individuals with measurements collected between 1999 and 2008. Mean ICAM-1 and VCAM-1 levels were 288±87 ng/mL and 999±407 ng/mL. Higher ICAM-1 and VCAM-1 were observed with increases in PM2.5. A 1 standard deviation (SD) increase in a 2 day moving average of PM2.5 (equivalent to 5.6 ug/m^3) was associated with 1.8% (95% Confidence Interval (CI): 0.7, 3.0) and 3.0% (95% CI: 1.5, 4.6) higher ICAM-1 and VCAM-1 respectively. Significant differences in susceptibility by SNP-by-PM2.5 interactions were observed with several of the SNPs examined; particularly strong effects for both ICAM-1 and VCAM-1 were observed with SNPs in GEMIN4. For example, a 1 SD increase in PM among carriers of the non-synonymous SNP rs4968104 was associated with 3.0% 2.5 GEMIN4 (95% CI: 1.4, 4.6) higher ICAM-1 levels but only 0.6% (95% CI: -1.0, 2.2) higher levels in non-carriers (p-interaction=0.02) while for VCAM-1 we observed 4.9% (95% CI: 2.8, 7.0) higher levels among carriers of the variant but only 1.3% (95% CI: -0.7, 3.4) higher levels in non-carriers (p-interaction=.01).

Conclusions: We observed significant miRNA-processing SNP-by-PM2.5 interactions, suggesting a potential role for PM2.5 in inducing post-transcriptional modification as well as evidence of underlying variation in susceptibility to these effects. 
American Thoracic Society 2010 International Conference 
New Orleans, LA 
May 14-19, 2010