️4: Shaping the Heart: How CXCL12 Drives Coronary Artery Anatomy

️ Episode 4: Shaping the Heart: How CXCL12 Drives Coronary Artery Anatomy In this episode of Base by Base, we explore a groundbreaking 2025 study published in Cell that reveals how the gene CXCL12 contributes to natural variation in coronary artery anatomy across diverse human populations. The study identifies CXCL12 as a key regulator of coronary artery dominance — a developmental trait that determines whether the right, left, or both coronary arteries perfuse the posterior heart.Combining large-scale genome-wide association studies (GWAS) in over 60,000 individuals from the Million Veteran Program with in vivo validations in fetal human hearts and knockout mouse models, the authors uncover how common genetic variants influence arterial patterning during development. Key insights include:GWAS reveals 10 loci associated with coronary dominance, with CXCL12 as the top signal in both European and African ancestry groups.CXCL12 is expressed in fetal coronary arteries precisely at the stage when dominance is established.Reducing Cxcl12 expression in mice alters coronary branching and septal dominance, supporting its role in early arterial patterning.Deep learning and chromatin accessibility analyses suggest that regulatory variants affect CXCL12 expression through transcription factor binding disruption.Colocalization of CXCL12-linked dominance variants with coronary artery disease (CAD) loci suggests shared developmental and pathological pathways.This episode highlights how developmental genetics can inform cardiovascular risk and inspire strategies for “medical revascularization” by targeting early-life vascular programming. Reference:Rios Coronado, P.E., Zhou, J., Fan, X., et al. (2025). CXCL12 drives natural variation in coronary artery anatomy across diverse populations. Cell, 188(7), 1784–1806. https://doi.org/10.1016/j.cell.2025.02.005 License: This content is distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). For more information, visit https://creativecommons.org/licenses/by/4.0/

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