Fig 5. SMAD3 expression is directly correlated with disease risk.

A) HCASMC eQTL data was employed to investigate the directionality of associated disease variation on SMAD3 expression in a highly disease relevant cellular model. The disease risk C allele genotype at rs17293632 was associated with increased SMAD3 expression. This genotype effect on expression was significant at p<0.05 employing a linear regression model. B) To investigate all variation that might contribute to differential expression of SMAD3 and thus disease risk, we studied CAD associated SNPs from the latest CARDIOGRAM+C4D meta-analysis [7] that were associated with CAD at p<1.0e-6 and that were located up to 100kb away from the SMAD3 gene. This regression analysis with HCASMC eQTL data had a Perrson correlation coefficient of 0.45 and was nominally significant at p = 0.08, suggesting that SMAD3 expression increases with a greater number of cis-risk alleles as per an additive model and further implicate SMAD3 expression and function in disease risk in this cell type. C) All CAD associated SNPs at p<1.0e-4 from Nelson et al. [7] that were identified in the cis-eQTL summary results, having some association with SMAD3 expression levels in artery tissues (internal mammary artery; MAM) in individuals with CAD from the STARNET study were plotted relative to each other based on their respective effect sizes (log OR) [60]. Pearson correlation coefficient R = 0.894, p = 3.76e-9.