Multi-ethnic analysis reveals soluble L-selectin may be post-transcriptionally regulated by 3'UTR polymorphism: the Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract

L-Selectin is constitutively expressed on leukocytes and mediates their interaction with endothelial cells during inflammation. Previous studies on the association of soluble L-selectin (sL-selectin) with cardiovascular disease (CVD) are inconsistent. Genetic variants associated with sL-selectin levels may be a better surrogate of levels over a lifetime. We explored the association of genetic variants and sL-selectin levels in a race/ethnicity stratified random sample of 2,403 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Through a genome-wide analysis with additive linear regression models, we found that rs12938 on the SELL gene accounted for a significant portion of the protein level variance across all four races/ethnicities. To evaluate potential additional associations, elastic net models were used for variants located in the SELL/SELP/SELE genetic region and an additional two SNPs, rs3917768 and rs4987361, were associated with sL-selectin levels in African Americans. These variants accounted for a portion of protein variance that ranged from 4 % in Hispanic to 14 % in African Americans. To investigate the relationship of these variants with CVD, 6,317 subjects were used. No significant association was found between any of the identified SNPs and carotid intima-media thickness or presence of carotid plaque using linear and logistic regression, respectively. Similarly no significant results were found for coronary artery calcium or coronary heart disease events. In conclusion, we found that variants within the SELL gene are associated with sL-selectin levels. Despite accounting for a significant portion of the protein level variance, none of the variants was associated with clinical or subclinical CVD.

Figure 1

LocusZoom plots of the SNP associations with soluble L-selectin in proximity to SELL polymorphism rs12938 by race/ethnicity. Color of each SNP is indicative of linkage disequilbrium with rs12938. Significance threshold (1e-05) is indicated by dashed gray line. SELL polymorpism rs1131498 (previously reported to be associated with CHD) is additionally labeled.

Figure 2

LocusZoom plot of SELL/SELP/SELE genetic region for the African American cohort, with rs12938 the reference SNP. Additional SNPs selected by the elastic net model (rs, rs) are also labeled.