CXCL12 regulates coronary artery dominance in diverse populations and links development to disease
Author:
Rios Coronado Pamela EORCID, Zanetti DanielaORCID, Zhou JiayanORCID, Naftaly Jeffrey AORCID, Prabala PratimaORCID, Kho Pik FangORCID, Martínez Jaimes Azalia MORCID, Hilliard Austin TORCID, Pyarajan Saiju, Dochtermann DanielORCID, Chang Kyong-MiORCID, Winn Virginia DORCID, Pașca Anca MORCID, Plomondon Mary EORCID, Waldo Stephen W, Tsao Philip S, Clarke Shoa L.ORCID, Red-Horse KristyORCID, Assimes Themistocles L.ORCID,
Abstract
AbstractMammalian cardiac muscle is supplied with blood by right and left coronary arteries that form branches covering both ventricles of the heart. Whether branches of the right or left coronary arteries wrap around to the inferior side of the left ventricle is variable in humans and termed right or left dominance. Coronary dominance is likely a heritable trait, but its genetic architecture has never been explored. Here, we present the first large-scale multi-ancestry genome-wide association study of dominance in 61,043 participants of the VA Million Veteran Program, including over 10,300 Africans and 4,400 Admixed Americans. Dominance was moderately heritable with ten loci reaching genome wide significance. The most significant mapped to the chemokineCXCL12in both Europeans and Africans. Whole-organ imaging of human fetal hearts revealed that dominance is established during development in locations whereCXCL12is expressed. In mice, dominance involved the septal coronary artery, and its patterning was altered with Cxcl12 deficiency. Finally, we linked human dominance patterns with coronary artery disease through colocalization, genome-wide genetic correlation and Mendelian Randomization analyses. Together, our data supportsCXCL12as a primary determinant of coronary artery dominance in humans of diverse backgrounds and suggests that developmental patterning of arteries may influence one’s susceptibility to ischemic heart disease.
Publisher
Cold Spring Harbor Laboratory
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