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Published on: April 13, 2015
CXCL12 drives natural variation in coronary artery anatomy across diverse populations
Pamela E Rios Coronado1, Jiayan Zhou2, Xiaochen Fan1
1Department of Biology, Stanford University, Stanford, CA, USA.
Insights
This study reveals that the gene CXCL12 plays a key role in determining coronary artery patterns in humans. Targeting this gene could lead to new treatments for heart conditions by influencing blood vessel development.
Area of Science:
- Cardiovascular Genetics
- Developmental Biology
- Human Anatomy
Background:
- Coronary artery branching patterns exhibit natural variation, notably in coronary dominance, affecting heart muscle perfusion.
- Coronary dominance describes how the inferior/posterior left heart is supplied by the right, left, or both coronary arterial trees.
Purpose of the Study:
- To investigate the genetic basis of coronary dominance using a large-scale genome-wide association study.
- To identify specific genes and pathways involved in the developmental patterning of human coronary arteries.
Main Methods:
- Genome-wide association study (GWAS) on angiographic data from over 60,000 US veterans of diverse ancestry.
- Analysis of gene expression (CXCL12) in human fetal hearts and functional studies in mouse models.
Main Results:
- Identified ten significant genetic loci associated with coronary dominance, indicating moderate heritability.
- The strongest association was found near the CXCL12 gene in both European and African ancestry cohorts.
- CXCL12 expression in fetal hearts correlates with dominance establishment; reducing Cxcl12 in mice altered coronary patterns.
Conclusions:
- CXCL12 is a key regulator of human coronary artery patterning during development.
- These findings suggest potential therapeutic strategies for cardiovascular diseases by targeting developmental pathways like CXCL12 for 'medical revascularization'.
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.
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