Abstract P250: Thr715pro Polymorphism in the Platelet Selectin Gene Does Not Modify Effects of Air Pollution Exposure.
Authors: Wittkopp Sharine , Staimer Norbert , Tjoa Thomas , Gillen Daniel L , Daher Nancy , Shafer Martin M , Schauer James J , Sioutas Constantinos , Delfino Ralph J 
Published: July 2021

Background:
Epidemiological and toxicological studies support an adverse effect of air pollution exposure on cardiovascular outcomes, and proposed mechanisms include increased thrombosis and coagulation. Previously, we showed increased plasma levels of soluble platelet selectin (sP-selectin) and increased expression of the platelet selectin gene (
SELP
) in association with higher air pollution exposure; both indicating probable increased platelet activation. A functional polymorphism in
SELP
, Thr715Pro, decreases circulating levels of sP-selectin and is associated with decreased risk for venous thromboembolism and myocardial infarction. We hypothesized that carriers of the Pro allele would have weaker associations of gene expression and protein level with air pollution exposure versus non-carriers.

Methods:
We used a cohort-panel design, with repeated measures of exposures and outcomes among 60 elderly, non-smoking subjects with coronary artery disease, living in the Los Angeles air basin. This population is shown to have higher susceptibility to pollutant exposure. We measured plasma sP-selectin levels weekly for all 60 subjects using an ELISA assay. Genotypes were determined using restriction fragment length polymorphism analysis. Whole blood gene expression levels were measured using quantitative polymerase chain reactions, for a subset of 40 subjects. Pollutant exposures measured at subject residences included the following: NO
2
/NO
x
, O
3
, CO, PM
2.5
organic, elemental and black carbon; particulate matter size fractions (PM
0.25
, PM
0.25-2.5
, PM
2.5-10
); and organic components and oxidative potential of PM. Primary and secondary organic carbon were estimated from total organic carbon. T-tests and linear mixed effects models were used to analyze the data.

Results:
We determined that the 12 subjects who were carriers of the protective, Pro715, allele had lower sP-selectin levels versus Thr715 homozygotes (34.78 ng/mL vs 42.03 ng/mL, p<0.001 by t-test). Pro715 allele carriers also had 0.396-fold lower
SELP
expression versus Thr715 homozygotes (p<0.005). However, in pollutant models, there was no significant interaction between carrier status and pollutant level (p-value= 0.1 or greater).

Conclusions:
While it appears that both
SELP
gene and protein expression increases in association with air pollution exposure and these levels are lower in Pro715 carriers, we found no effect modification of these relationships by genotype. Recent data suggests that lower plasma sP-selectin in 715Pro carriers results from decreased N-glycosylation and subsequent sequestration in the Golgi apparatus. To our knowledge, there is no data indicating that N-glycosylation changes as a result of air pollution exposure. We conclude that differences in the soluble protein levels due to the presence of this polymorphism are not altered as a result of changes in air pollution exposure.