CXCL12 drives natural variation in coronary artery anatomy across diverse populations.

Autor:	Rios Coronado PE; Department of Biology, Stanford University; Stanford, CA, USA., Zanetti D; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine; Stanford, CA, USA.; VA Palo Alto Health Care System; Palo Alto, CA, USA.; Institute of Genetic and Biomedical Research, National Research Council; Cagliari, Sardinia, Italy., Zhou J; VA Palo Alto Health Care System; Palo Alto, CA, USA.; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine; Stanford, CA, USA., Naftaly JA; Department of Biology, Stanford University; Stanford, CA, USA., Prabala P; Department of Biology, Stanford University; Stanford, CA, USA., Martínez Jaimes AM; Department of Developmental Biology, Stanford University School of Medicine; Stanford, CA, USA.; Department of Biology, Stanford University; Stanford, CA, USA., Farah EN; Department of Medicine, Division of Cardiology, University of California San Diego; La Jolla, CA, USA., Fan X; Department of Biology, Stanford University; Stanford, CA, USA., Kundu S; Department of Genetics, Stanford University School of Medicine; Stanford, CA, USA.; Department of Computer Science, Stanford University; Stanford, CA, USA., Deshpande SS; Institute for Computational and Mathematical Engineering, Stanford University School of Medicine; Stanford, CA, USA., Evergreen I; Department of Genetics, Stanford University School of Medicine; Stanford, CA, USA., Kho PF; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine; Stanford, CA, USA.; VA Palo Alto Health Care System; Palo Alto, CA, USA., Hilliard AT; VA Palo Alto Health Care System; Palo Alto, CA, USA., Abramowitz S; Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA.; Sarnoff Cardiovascular Research Foundation; McLean, VA, USA.; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell; Hempstead, NY, USA., Pyarajan S; Center for Data and Computational Sciences, VA Boston Healthcare System; Boston, MA, USA., Dochtermann D; Center for Data and Computational Sciences, VA Boston Healthcare System; Boston, MA, USA., Damrauer SM; Corporal Michael J. Crescenz VA Medical Center; Philadelphia, PA, USA.; Department of Surgery, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA.; Department of Genetics, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA., Chang KM; Corporal Michael J. Crescenz VA Medical Center; Philadelphia, PA, USA.; Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA., Levin MG; Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA, USA.; Corporal Michael J. Crescenz VA Medical Center; Philadelphia, PA, USA., Winn VD; Department of Obstetrics and Gynecology, Stanford University School of Medicine; Stanford, CA, USA., Paşca AM; Department of Pediatrics, Neonatology, Stanford University School of Medicine; Stanford, CA, USA., Plomondon ME; Department of Medicine, Rocky Mountain Regional VA Medical Center; Aurora, CO, USA.; CART Program, VHA Office of Quality and Patient Safety; Washington, DC, USA., Waldo SW; Department of Medicine, Rocky Mountain Regional VA Medical Center; Aurora, CO, USA.; CART Program, VHA Office of Quality and Patient Safety; Washington, DC, USA.; Division of Cardiology, University of Colorado School of Medicine; Aurora, CO, USA., Tsao PS; VA Palo Alto Health Care System; Palo Alto, CA, USA.; Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA.; Cardiovascular Institute, Stanford University School of Medicine; Stanford, CA, USA., Kundaje A; Department of Genetics, Stanford University School of Medicine; Stanford, CA, USA.; Department of Computer Science, Stanford University; Stanford, CA, USA., Chi NC; Department of Medicine, Division of Cardiology, University of California San Diego; La Jolla, CA, USA., Clarke SL; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine; Stanford, CA, USA.; VA Palo Alto Health Care System; Palo Alto, CA, USA.; Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine; Stanford, CA, USA., Red-Horse K; Department of Biology, Stanford University; Stanford, CA, USA.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Stanford, CA, USA.; Howard Hughes Medical Institute; Chevy Chase, MD, USA., Assimes TL; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine; Stanford, CA, USA.; VA Palo Alto Health Care System; Palo Alto, CA, USA.; Cardiovascular Institute, Stanford University School of Medicine; Stanford, CA, USA.; Department of Epidemiology and Population Health, Stanford University School of Medicine; Stanford, CA, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Jul 05. Date of Electronic Publication: 2024 Jul 05.
DOI:	10.1101/2023.10.27.23297507
Abstrakt:	To efficiently distribute blood flow to cardiac muscle, the coronary artery tree must follow a specific branching pattern over the heart. How this pattern arises in humans is unknown due to the limitations of studying human heart development. Here, we leveraged a natural variation of coronary artery anatomy, known as coronary dominance, in genetic association studies to identify the first known driver of human coronary developmental patterning. Coronary dominance refers to whether the right, left, or both coronary arteries branch over the posterior left ventricle, but whether this variability is heritable and how it would be genetically regulated was completely unknown. By conducting the first large-scale, multi-ancestry genome-wide association study (GWAS) of coronary dominance in 61,043 participants of the VA Million Veteran Program, we observed moderate heritability (27.7%) with ten loci reaching genome wide significance. An exceptionally strong association mapped DNA variants to a non-coding region near the chemokine CXCL12 in both European and African ancestries, which overlapped with variants associated with coronary artery disease. Genomic analyses predicted these variants to impact CXCL12 levels, and imaging revealed dominance to develop during fetal life coincident with CXCL12 expression. Reducing Cxcl12 in mice to model the human genetics altered septal artery dominance patterns and caused coronary branches to develop away from Cxcl12 expression domains. Cxcl12 heterozygosity did not compromise overall artery coverage as seen with full deletion, but instead changed artery patterning, reminiscent of the human scenario. Together, our data support CXCL12 as a critical determinant of human coronary artery growth and patterning and lay a foundation for the utilization of developmental pathways to guide future precision 'medical revascularization' therapeutics. Competing Interests: Competing interests: A.K. is on the scientific advisory board of SerImmune, TensorBio and OpenTargets, and a consultant with Arcadia Science and Inari Agriculture. A.K. was a scientific co-founder of RavelBio, a paid consultant with Illumina, was on the SAB of PatchBio and owns shares in DeepGenomics, Immunai, Freenome, and Illumina. All other authors declare they have no competing interests.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu