The heart requires an efficient network of coronary arteries to provide continuous perfusion with oxygenated blood while pumping. Researchers have little insight into the human process of coronary artery development despite its critical role within the body. The human heart comprises a standard coronary system in which the left main coronary artery (LCA) originates from the left side of the aorta and is followed through the left anterior descending (LAD) and left circumflex (LCx) arteries, which supply blood to the anterior and left lateral wall of the ventricle, respectively. The right coronary artery (RCA) branches off from the right side of the aorta and moves around the right ventricle towards the posterior part of the heart. Other than coronary anomalies, which have the potential to lead to adverse cardiovascular consequences, the origins and courses of the LCA, LAD, LCx, and RCA are identical across the population.
Coronary artery dominance is a key anatomical variation that determines which artery supplies blood to the posterior section of the heart through the posterior descending artery (PDA). The PDA vessel originates from the RCA in 80% of cases, develops from the LCx in 10% of cases, and arises from both RCA and LCx simultaneously in the remaining 10% population. The research investigated the genetic origins of normal heart variations by performing a large-scale genome-wide association study (GWAS).
The research leveraged data from over 61,000 genotyped individuals in the Million Veteran Program (MVP), all of whom underwent invasive coronary angiography. Researchers performed a multi-ancestry GWAS investigation through analysis of the Trans-Omics for Precision Medicine (TOPMed) reference panel data.
Research results demonstrated that CXCL12 acts as a key gene involved in determining coronary heart disease dominance apart from being already connected to coronary artery disease (CAD). According to genomic control lambda values, there was no indication that population stratification affected common variants (MAF > 0.01). Research-based on estimating SNP-based narrow-sense heritability (h²) found 0.277 for EUR populations (95% CI: 0.150-0.404) through the GCTA and GREML-LDMS-I method when non-right dominance was expected at 17%. Most of the genetic variance was attributed to rare polymorphic variants.
The genetic research through ancestry-based examinations and combined analysis located ten important genetic spots that reached genome-wide statistical significance in seven chromosomes. Genome-wide significance was reached by seven loci specifically among datasets with more than 2,000 non-right dominant individuals.
The formation of arteries depends critically on Cxcl12, according to previous experimental work using both zebrafish and mice as animal models. The gene functions as a chemoattractant to bring pre-arterial endothelial cells (ECs), which form mature arteries. The outflow tract, together with the myocardium and epicardium in developing mouse hearts, produces Cxcl12 to attract CXCR4-expressing ECs through cell receptivity. These migrating cells move against the direction of blood flow to reach artery-lengthening positions. These cells migrate against blood flow to elongate arteries, a mechanism believed to mirror what occurs during human coronary development.
Scientific research showed that genomic variations near CXCL12 impact transcription factor binding potential, thus affecting the developmental processes of the RCA. The reduced expression of CXCL12 might slow down RCA development, which prompts the LCA to take over and create left-dominant anatomy. The strong colocalization between the CXCL12 locus and coronary artery disease behavior caused experts to question whether these patterns indicate a shared biological pathway (vertical pleiotropy) or independent genetic effects (horizontal pleiotropy). The research explores important clinical doubts about whether coronary artery dominance influences risk factors for heart diseases or treatment results.
Historical data suggests that patients with left dominant coronary arteries develop more serious conditions after experiencing myocardial infarctions because their coronary circulation remains asymmetrical. A few investigations have detected that cardiac dominance patterns right of the heart could exhibit advanced levels of atherosclerosis. People with left or co-dominant coronary artery anatomies may have lower plaque formation risk but face greater danger during myocardial infarction.
This groundbreaking study proved that genetic regulation of CXCL12 contributes to coronary artery dominance patterns as it demonstrates that natural heart structures have genetic regulation. The discovery creates new possibilities to examine developmental factors affecting cardiovascular health in adults together with potential applications for individualized medical approaches.
References: Rios Coronado PE, Zhou J, Fan X, et al. CXCL12 drives natural variation in coronary artery anatomy across diverse populations. Cell. 2025;188(7):1784-1806.e22. doi:10.1016/j.cell.2025.02.005
