CXCL12 drives natural variation in coronary artery anatomy across diverse populations

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

CXCL12 drives natural variation in coronary artery anatomy across diverse populations

Pamela E Rios Coronado et al. Cell. 2025.

. 2025 Apr 3;188(7):1784-1806.e22.

doi: 10.1016/j.cell.2025.02.005. Epub 2025 Mar 5.

Authors

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests A.K. is on the scientific advisory board (SAB) of SerImmune, TensorBio, and OpenTargets and is a consultant with Arcadia Science and Inari Agriculture. A.K. was a scientific co-founder of RavelBio, a paid consultant with Illumina, was on the SAB of PatchBio, and owns shares in DeepGenomics, Immunai, Freenome, and Illumina.

Update of

CXCL12 drives natural variation in coronary artery anatomy across diverse populations.
Rios Coronado PE, Zanetti D, Zhou J, Naftaly JA, Prabala P, Martínez Jaimes AM, Farah EN, Fan X, Kundu S, Deshpande SS, Evergreen I, Kho PF, Hilliard AT, Abramowitz S, Pyarajan S, Dochtermann D; Million Veteran Program; Damrauer SM, Chang KM, Levin MG, Winn VD, Paşca AM, Plomondon ME, Waldo SW, Tsao PS, Kundaje A, Chi NC, Clarke SL, Red-Horse K, Assimes TL. Rios Coronado PE, et al. medRxiv [Preprint]. 2024 Jul 5:2023.10.27.23297507. doi: 10.1101/2023.10.27.23297507. medRxiv. 2024. Update in: Cell. 2025 Apr 03;188(7):1784-1806.e22. doi: 10.1016/j.cell.2025.02.005. PMID: 37961706 Free PMC article. Updated. Preprint.

References

1. Baroldi G, Scomazzoni G, and United States. Surgeon-General’s, O. (1967). Coronary circulation in the normal and the pathologic heart (Office of the Surgeon General, Dept. of the Army; for sale by the Superintendent of Documents, U.S. Govt. Print. Off.).
1. Libby P, Bonow RO, Mann DL, Tomaselli GF, Bhattt DL, and Solomon S (2021). Braunwald’s heart disease : a textbook of cardiovascular medicine, 12. Edition (Elsevier; ).
1. Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Barone Gibbs B, Beaton AZ, Boehme AK, et al. (2024). 2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation 149, e347–e913. 10.1161/CIR.0000000000001209. - DOI - PubMed
1. Thiene G, Frescura C, Padalino M, Basso C, and Rizzo S (2021). Coronary Arteries: Normal Anatomy With Historical Notes and Embryology of Main Stems. Front Cardiovasc Med 8, 649855. 10.3389/fcvm.2021.649855. - DOI - PMC - PubMed
1. Bruell JH, Leininger JT, and Hellerstein HK (1970). Inheritance of a cardiac arterial asymmetry in mice. Science (New York, N.Y 167, 199–200. 10.1126/science.167.3915.199. - DOI - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

CXCL12 drives natural variation in coronary artery anatomy across diverse populations

Affiliations

CXCL12 drives natural variation in coronary artery anatomy across diverse populations

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases