Abstract Body:
Diabetes increases risk of Coronary Artery Disease (CAD) 2-4x and 68% of all mortality in diabetic patients is attributed to heart disease. Genome-wide association studies (GWAS) have identified >1500 loci independently associated with CAD, T2D, or T1D. Importantly, concordant genomic regions associated across these diseases and shared clinical features suggest convergent genetic architectures across these conditions. Further investigation of the genetic drivers of CAD, T2D, and T1D will unravel the genetic architecture of cardiometabolic disease risk and inform novel therapeutic intervention.

Genetic colocalization analysis with approximate bayes factorization was performed on three largest available CAD, T2D, and T1D GWAS summary statistics. Significant loci were mapped to genes ± 10 kb of gene TSS and overlapped with GTEx coronary artery expression quantitative trait loci (eQTL). Multi-marker Analysis of GenoMic Association (MAGMA) was performed for each study. Significant genes were further queried by plaque features (lesion stage, calcification) in a multi-modal single cell atlas of atherosclerosis (MetaPlaq) and plaque expression was associated with molecular features and clinical outcomes in the Athero-Express biobank (n=2,595).

We identified significant colocalization for 161 SNPs (158 genes) and 47 SNPs (45 genes) across CAD/ T2D and CAD/ T1D respectively. Of note, we identified 21 genes colocalized across all three traits. Among these, VEGFA colocalized in CAD/ T2D, and was upregulated in advanced atherosclerotic plaques in vascular smooth muscle cells (VSMC) and was associated with upregulation of plaque inflammatory markers (IL6, IL8, slCAM1), increased body fat percentage, and was nominally associated with cardiovascular death in Athero-Express. An INPP5B-associated SNP was colocalized in CAD/ T1D and was identified as a significant coronary artery eQTL in GTEx. INPP5B was also upregulated in monocytes and plaque expression level was correlated with IL6 expression in advanced plaques. INPP5B plaque expression was inversely correlated with incidence of major clinical episodes and cardiovascular death.

Together, these analyses identify novel shared features among CAD, T2D, and T1D. Investigation of candidate genes reveal associations with differential expression in relevant cell types, patient features, and clinical outcomes. Ongoing efforts involving functional validation will identify emerging targets with therapeutic benefits across disease.