CXCL12 drives natural variation in coronary artery anatomy across diverse populations
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.
Authors
- C. Neil (ORCID: https://orcid.org/0000-0003-2324-3796)
- Qixuan Ma (ORCID: https://orcid.org/0000-0002-5521-6699)
- Jeffrey A. Naftaly (ORCID: https://orcid.org/0000-0002-8981-0063)
- Jiayan Zhou (ORCID: https://orcid.org/0000-0001-5974-087X)
- Themistocles L. Assimes (ORCID: https://orcid.org/0000-0003-2349-0009)
- Stephen W. Waldo (ORCID: https://orcid.org/0000-0003-0678-4873)
- Xiaochen Fan (ORCID: https://orcid.org/0000-0002-4316-0616)
- Pamela E. Rios Coronado (ORCID: https://orcid.org/0000-0003-4665-6438)
- Pik Fang Kho (ORCID: https://orcid.org/0000-0001-7831-6062)
- Daniela Zanetti (ORCID: https://orcid.org/0000-0002-1225-1021)
- Kyong‐Mi Chang (ORCID: https://orcid.org/0000-0001-6811-9364)
- Virginia D. Winn (ORCID: https://orcid.org/0000-0003-1136-2907)
- Mary E. Plomondon (ORCID: https://orcid.org/0000-0002-8616-4916)
- Saiju Pyarajan (ORCID: https://orcid.org/0000-0002-9047-3762)
- Philip S. Tsao (ORCID: https://orcid.org/0000-0001-7274-9318)
- Anca M. Pașca (ORCID: https://orcid.org/0000-0002-0445-9009)
- Sarah Abramowitz (ORCID: https://orcid.org/0000-0001-5515-1752)
- Kristy Red‐Horse (ORCID: https://orcid.org/0000-0003-1541-601X)
- Michael G. Levin (ORCID: https://orcid.org/0000-0002-9937-9932)
- Daniel Dochtermann (ORCID: https://orcid.org/0000-0001-9513-5124)
- Shoa L. Clarke (ORCID: https://orcid.org/0000-0002-6592-1172)
- Scott M. Damrauer (ORCID: https://orcid.org/0000-0001-8009-1632)
- Anshul Kundaje (ORCID: https://orcid.org/0000-0003-3084-2287)
- Elie N. Farah (ORCID: https://orcid.org/0000-0002-2412-0950)
- Austin T. Hilliard (ORCID: https://orcid.org/0000-0002-1289-4377)
- Azalia M. Martínez Jaimes (ORCID: https://orcid.org/0000-0001-9412-6787)
- Pratima Prabala (ORCID: https://orcid.org/0000-0001-6436-6907)
- Ivy Evergreen (ORCID: https://orcid.org/0009-0004-6737-889X)
- Soumya Kundu
- Salil Deshpande (ORCID: https://orcid.org/0009-0009-5776-8428)
Institutions
- Howard Hughes Medical Institute (US)
- VA Palo Alto Health Care System (US)
- Cardiovascular Institute of the South (US)
- VA Boston Healthcare System (US)
- University of California San Diego (US)
- Stanford Health Care (US)
- Donald & Barbara Zucker School of Medicine at Hofstra/Northwell (US)
- Institute of Genetic and Biomedical Research (IT)
- Philadelphia VA Medical Center (US)
- Stanford Medicine (US)
- Sarnoff Cardiovascular Research Foundation (US)
- National Research Council (IT)
- Rocky Mountain MS Center (US)
- University of Pennsylvania (US)
- National Patient Safety Foundation (US)
- University of Colorado Denver (US)
- Stanford University (US)
Publication Details
- Journal
- Cell
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1016/j.cell.2025.02.005
- Citations
- 8
- Primary Topic
- Atherosclerosis and Cardiovascular Diseases
- Type
- article
- Field-Weighted Citation Impact
- 6.38
Funders
- Howard Hughes Medical Institute
- U.S. Department of Veterans Affairs
- National Heart, Lung, and Blood Institute