CXCL12 drives natural variation in coronary artery anatomy across diverse populations
Pamela E. Rios Coronado, Jiayan Zhou, Xiaochen Fan, Daniela Zanetti, Jeffrey A. Naftaly, Pratima Prabala, Azalia M. Martínez Jaimes, Elie N. Farah, Soumya Kundu, Salil Deshpande, Ivy Evergreen, Pik Fang Kho, Qixuan Ma, Austin T. Hilliard, Sarah Abramowitz, Saiju Pyarajan, Daniel Dochtermann, Scott M. Damrauer, Kyong‐Mi Chang, Michael G. Levin, Virginia D. Winn, Anca M. Pașca, Mary E. Plomondon, Stephen W. Waldo, Philip S. Tsao, Anshul Kundaje, Neil C. Chi, Shoa L. Clarke, Kristy Red‐Horse, Themistocles L. Assimes
Abstract
Coronary arteries have a specific branching pattern crucial for oxygenating heart muscle. Among humans, there is natural variation in coronary anatomy with respect to perfusion of the inferior/posterior left heart, which can branch from either the right arterial tree, the left, or both-a phenotype known as coronary dominance. Using angiographic data for >60,000 US veterans of diverse ancestry, we conducted a genome-wide association study of coronary dominance, revealing moderate heritability and identifying ten significant loci. The strongest association occurred near CXCL12 in both European- and African-ancestry cohorts, with downstream analyses implicating effects on CXCL12 expression. We show that CXCL12 is expressed in human fetal hearts at the time dominance is established. Reducing Cxcl12 in mice altered coronary dominance and caused septal arteries to develop away from Cxcl12 expression domains. These findings indicate that CXCL12 patterns human coronary arteries, paving the way for "medical revascularization" through targeting developmental pathways.