Abstract 16503: C-X-C Motif Chemokine Ligand 12 is a Primary Determinant of Coronary Artery Dominance

Abstract

Introduction: Left coronary dominance is associated with worse clinical outcomes in the setting of coronary artery disease (CAD). Little is known about the determinants of dominance, including whether it is solidified in utero or sometime after birth. Hypothesis: Investigating the genetic determinants of dominance will identify new arteriogenesis pathways targetable for enhancing coronary artery growth and collateralization in humans. Methods: We conducted a stratified multi-population genome-wide association study of dominance using REGENIE and TopMed-imputed genotypes available in 43813 White, 9532 Black, and 3550 Hispanic participants of the Million Veteran Program (MVP) who had undergone a cardiac catheterization. We modelled left and co-dominant combined vs. right, as well as left vs. right dominance, adjusting for sex and 10 genetic principal components. We also explored whether dominance and CAD were genetically correlated using LD score regression. Lastly, we sought to validate compelling population genetic signals in mice using whole organ imaging of the heart, which allows for the quantification of coronary anatomy and variation. Results: Thirteen loci reached genome wide significance (GWS). The most intriguing was a top hit located downstream of C-X-C Motif Chemokine Ligand 12 (CXCL12) which, remarkably, reached GWS in both White and Black Veterans. While the CXCL12 signal robustly colocalized with the signal in this region for CAD (COLOC PPH4: 87.1%), the genome wide genetic correlation of dominance with CAD was otherwise modest in both MVP (rg=-0.18, p=0.007) and CardiogramplusC4D (rg=-0.16, p=0.018). To gain evidence for causality, we modeled dominance in Cxcl12-deficient mice (n=64 wildtype; n=62 heterozygous). Murine coronary arteries develop in a field of Cxcl12 expression and choose right or left dominance during embryogenesis, a time when we found human dominance to also be evident. Reminiscent of our human GWAS, dominance was skewed away from the common phenotype in Cxcl12 heterozygous mice (p=0.038). Conclusions: CXCL12 is a primary determinant of coronary artery dominance in humans and mice. The modest negative genetic correlation between CAD and dominance supports a developmental component to CAD susceptibility.