Angiopoeitin-2 as a Biomarker for Gene-Environment Interactions in a Cardiovascular Disease Cohort
Jiangda Ou1, Janet Huebner1, Cavin Ward-Caviness2, Robert B. Devlin2, Lucas M. Neas2, David Diaz-Sanchez2, Wayne E. Cascio2, Elizabeth R. Hauser1, William E. Kraus1
1 Duke University, Durham, NC; 2 US EPA, Chapel Hill, NC
Background: We are investigating the effects of acute and chronic air pollution exposure on cardiovascular disease using the 9323-member Duke CATHGEN cohort of individuals undergoing coronary artery catheterization (collected 2001-2011) — CATHGEN includes individuals with and without coronary atherosclerosis. We have shown that air quality, including distance-to-roadway (DTR), PM2.5, and ozone are associated with presence of chronic cardiovascular disease and acute cardiovascular events; in addition, specific genetic variants mediate some of these associations. We are continuing to evaluate these relationships using specific disease biomarkers, peripheral blood gene expression, and circulating metabolic intermediates. Previous studies in CATHGEN identified an association between peripheral vascular disease (PVD) and distance-to-roadway (DTR), along with a genome-wide significant interaction with SNP rs755249 in the BMP8a gene. We hypothesized that these relationships would also be apparent as associations with angiopoietin-2 (Ang2), a biomarker associated with PVD and other cardiovascular diseases.
Methods: Concentrations of Ang2 in human plasma samples (n=2,226) from the CATHGEN cohort were quantified using a sandwich immunoassay (MesoScale Discovery Cat #K151KCD-1; Gaithersburg, MD). Genotyping was performed in CATHGEN participants using the Illumina HumanOmni 1-Quad_v1-0_C array. Geocoded primary residential address information was obtained for CATHGEN participants residing in North Carolina. The perpendicular distance between each primary residence and the nearest primary or secondary roadway was used as the distance to the nearest roadway measure (DTR) of traffic exposure. Race stratified linear regression models were fit to Ang2 plasma concentrations, DTR, genotype and the interaction between DTR and genotype, with adjustment for age, sex, genetic principal components and clinical covariates.
Results: A total of 1876 CATHGEN individuals lived in NC with both DTR and Ang2 measures. Consistent with previous analyses in CATHGEN, there was a trend for individuals with PVD to live closer on average to primary or secondary roadways (0.97 km versus 1.09 km, p=0.07). Mean Ang2 plasma concentrations were statistically significantly greater in individuals with PVD when compared with those without PVD (5817 pg/mL versus 4961 pg/mL, p=0.02 unadjusted and p=0.02 adjusted). There was no significant association of Ang2 with DTR (p=0.60). In the subset of 696 individuals with complete DTR, Ang2 and genotype data, the regression coefficient for the interaction between the rs755249 SNP in BMP8a and DTR on ANG2 was significantly different from 0 (p=0.014 unadjusted, p=0.049 adjusted, whites only).
Conclusions: Consistent with our previous findings in a PVD genome-wide interaction study, Ang2 plasma concentrations are associated with an interaction between DTR and rs755249 genotype. Ang2 may be a good biomarker for the impact of air quality and genotype on cardiovascular health in a high-risk population. However larger sample sizes will be required to untangle these complex relationships.
This abstract does not necessarily represent EPA policy.
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