Blood group antigen loci demonstrate multivariate genetic associations with circulating cellular adhesion protein levels in the Multi-Ethnic Study of Atherosclerosis

Abstract

The cellular adhesion pathway is critical in the pathophysiology of atherosclerosis, and genetic factors contributing to regulation of circulating levels of related proteins may be relevant to risk prediction of cardiovascular disease. In contrast to conducting separate genome-wide protein quantitative trait loci (pQTL) mapping analyses of each individual protein, joint genetic association analyses of multiple quantitative traits can leverage cross-trait co-variation and identify simultaneous regulatory effects on protein levels across the pathway. We conducted a multi-pQTL (mpQTL) analysis of 15 proteins related to cellular adhesion assayed on 2,313 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). We applied the MQFAM multivariate association analysis method in PLINK on normalized protein level residuals derived from univariate linear regression, adjusting for age, sex, and principal components of ancestry. Race/ethnicity-stratified analyses identified nine genome-wide significant (P<5e-08) loci associated with co-variation of protein levels. Although the majority of these SNPs were in proximity to structural genes of the assayed proteins, we discovered multiple loci demonstrating co-association with the circulation of at least two proteins. Of these, two significant loci specific to non-Hispanic white participants, rs17074898 at ALOX5AP (P = 1.78E-08) and rs7521237 at KIAA1614 (P = 2.2E-08), would not have met statistical significance using univariate analyses. Moreover, common patterns of multi-protein associations were discovered at the ABO locus across race/ethnicity. These results indicate the biological relevance of blood group antigens on regulation of circulating cellular adhesion pathway proteins while also demonstrating race/ethnicity-specific co-regulatory effects.

Secreted Protein Profiling of Human Aortic Smooth Muscle Cells Identifies Vascular Disease Associations

“…To date, most proteomics studies have been conducted using plasma samples from patients at higher risk for CVDs. [62][63][64][65][66] However, cell type-specific proteomic analyses using disease-relevant cells will be a valuable tool to dissect the origin of the proteome to accelerate the pathway to translation.…”

Secreted protein profiling of human aortic smooth muscle cells identifies vascular disease associations

“…Similarly, no functional study of LAMC2 has been carried out in the context of vascular biology and cardiovascular diseases; however, several studies showed its involvement in cancer [53][54][55][56][57] suggesting that LAMC2 plays a role in proliferation. To date, most proteomics studies have been conducted using plasma samples from patients at higher risk for cardiovascular diseases [58][59][60][61][62] . However, cell type-specific proteomic analyses using disease-relevant cells will be a valuable tool to dissect the origin of the proteome to accelerate the pathway to translation.…”