4: How CXCL12 Shapes Coronary Dominance

Rios Coronado PE et al., Cell - A multi-ancestry GWAS in >61,000 veterans identifies CXCL12 as a top locus influencing whether the right or left coronary tree supplies the posterior heart; fetal expression, spatial transcriptomics, deep-learning regulatory maps, and mouse heterozygous knockdown link CXCL12 regulation to coronary dominance. Key terms: CXCL12, coronary dominance, GWAS, fetal heart development, mouse model.

Study Highlights:
A GWAS of coronary dominance in 61,043 genotyped participants revealed moderate heritability and ten genome-wide significant loci, with the strongest signal near CXCL12 in both European- and African-ancestry groups. Genetic, eQTL, and deep-learning chromatin analyses indicate dominance-associated variants modulate CXCL12 regulatory elements and expression in vascular cell types. Spatial transcriptomics and fetal heart imaging show CXCL12 expression where dominance is established, and Cxcl12 haploinsufficiency in mice shifts septal artery dominance, supporting a causal role. The CXCL12 locus partially colocalizes with coronary artery disease signals, linking developmental patterning to adult disease risk.

Conclusion:
Common regulatory variation at the CXCL12 locus influences coronary artery patterning established in fetal development; modulating CXCL12 levels alters artery placement in mice and suggests developmental pathways could be targeted for revascularization.

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-04-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CXCL12 is the top GWAS signal for coronary dominance in EUR and AFR populations.
- CXCL12-CXCR4 signaling directs coronary artery development by chemoattraction of CXCR4-expressing pre-artery ECs toward CXCL12.
- Noncoding variants near CXCL12 modulate expression, causing reduced CXCL12 signaling and altered coronary patterning.
- Cxcl12 haploinsufficiency in mice shifts SpA (septal artery) dominance toward codominance, supporting a causal role for CXCL12 levels in arterial patterning.
- Dominance is established during fetal development with CXCL12 expressed in fetal hearts where dominance is set.
- Localized CXCL12 delivery could induce collateral arteries in humans, offering a path to medical revascularization, with emphasis on targeted delivery to minimize risks.

QC result: Pass.