CXCL12 drives natural variation in coronary artery anatomy across diverse populations.
Summary
A cross-ancestry GWAS of coronary dominance in >60,000 angiograms identified 10 loci, with the strongest signal near CXCL12. CXCL12 is expressed in human fetal hearts when dominance is set, and reducing Cxcl12 in mice shifts dominance and septal artery trajectories, establishing a developmental mechanism for coronary anatomy.
Key Findings
- GWAS of >60,000 angiograms identified 10 loci influencing coronary dominance with moderate heritability.
- Strongest association localized near CXCL12 across European- and African-ancestry cohorts, implicating CXCL12 expression.
- CXCL12 is expressed in human fetal hearts at the time dominance is established.
- Cxcl12 reduction in mice alters coronary dominance and redirects septal artery development.
Clinical Implications
Understanding genetic control of coronary dominance may inform pre-procedural planning, risk stratification for ischemia, and future concepts of "medical revascularization" by modulating developmental pathways.
Why It Matters
Links a specific chemokine pathway to human coronary patterning with convergent human genetics and mouse perturbation, opening a mechanistic basis for anatomical variability relevant to revascularization strategies.
Limitations
- Cohort drawn from US veterans may limit generalizability (e.g., sex and age distribution)
- Translational applications require further study to modulate developmental pathways safely
Future Directions
Map cellular targets and timing for CXCL12-mediated coronary patterning, evaluate genetic predictors of procedural outcomes, and explore pharmacologic modulation in preclinical models.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology/Diagnosis
- Evidence Level
- II - Large GWAS with experimental validation in animal models
- Study Design
- OTHER