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 S Deshpande; Ivy Evergreen; Pik Fang Kho; Qixuan Ma; Austin T Hilliard; Sarah Abramowitz; Saiju Pyarajan; Daniel Dochtermann; Million Veteran Program; Scott M Damrauer; Kyong-Mi Chang; Michael G Levin; Virginia D Winn; Anca M Paşca; Mary E Plomondon; Stephen W Waldo; Philip S Tsao; Anshul Kundaje; Neil C Chi; Shoa L Clarke; Kristy Red-Horse; Themistocles L Assimes

doi:10.1016/j.cell.2025.02.005

CXCL12 drives natural variation in coronary artery anatomy across diverse populations

Cell. 2025 Apr 3;188(7):1784-1806.e22. doi: 10.1016/j.cell.2025.02.005. Epub 2025 Mar 5.

Authors

Pamela E Rios Coronado¹, Jiayan Zhou², Xiaochen Fan¹, Daniela Zanetti³, Jeffrey A Naftaly¹, Pratima Prabala¹, Azalia M Martínez Jaimes⁴, Elie N Farah⁵, Soumya Kundu⁶, Salil S Deshpande⁷, Ivy Evergreen⁸, Pik Fang Kho⁹, Qixuan Ma⁵, Austin T Hilliard¹⁰, Sarah Abramowitz¹¹, Saiju Pyarajan¹², Daniel Dochtermann¹²; Million Veteran Program; Scott M Damrauer¹³, Kyong-Mi Chang¹⁴, Michael G Levin¹⁵, Virginia D Winn¹⁶, Anca M Paşca¹⁷, Mary E Plomondon¹⁸, Stephen W Waldo¹⁹, Philip S Tsao²⁰, Anshul Kundaje⁶, Neil C Chi⁵, Shoa L Clarke²¹, Kristy Red-Horse²², Themistocles L Assimes²³

Affiliations

¹ Department of Biology, Stanford University, Stanford, CA, USA.
² Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; VA Palo Alto Health Care System, Palo Alto, CA, USA.
³ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; VA Palo Alto Health Care System, Palo Alto, CA, USA; Institute of Genetic and Biomedical Research, National Research Council, Cagliari, Sardinia, Italy.
⁴ Department of Biology, Stanford University, Stanford, CA, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, CA, USA.
⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Department of Computer Science, Stanford University, Stanford, CA, USA.
⁷ Institute for Computational and Mathematical Engineering, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹¹ Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Sarnoff Cardiovascular Research Foundation, McLean, VA, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
¹² Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA.
¹³ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA; Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁴ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA; Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁵ Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
¹⁶ Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁷ Department of Pediatrics, Neonatology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸ Department of Medicine, Rocky Mountain Regional VA Medical Center, Aurora, CO, USA; CART Program, VHA Office of Quality and Patient Safety, Washington, DC, USA.
¹⁹ Department of Medicine, Rocky Mountain Regional VA Medical Center, Aurora, CO, USA; CART Program, VHA Office of Quality and Patient Safety, Washington, DC, USA; Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA.
²⁰ VA Palo Alto Health Care System, Palo Alto, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
²¹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; VA Palo Alto Health Care System, Palo Alto, CA, USA; Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA.
²² Department of Biology, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address: kredhors@stanford.edu.
²³ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; VA Palo Alto Health Care System, Palo Alto, CA, USA; Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: tassimes@stanford.edu.

PMID: 40049164
PMCID: PMC12029448 (available on 2026-04-03)
DOI: 10.1016/j.cell.2025.02.005

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.

Keywords: Cxcl12; GWAS; anatomy; coronary artery; dominance; heritability; human development; mouse models; population genetics; vascular patterning.

MeSH terms

Animals
Black People / genetics
Chemokine CXCL12* / genetics
Chemokine CXCL12* / metabolism
Coronary Vessels* / anatomy & histology
Coronary Vessels* / metabolism
Female
Genome-Wide Association Study
Humans
Male
Mice
Polymorphism, Single Nucleotide
White
White People / genetics

Substances

Chemokine CXCL12
CXCL12 protein, human

Abstract

MeSH terms

Substances

Grants and funding