ARHGEF26 – Coronary Artery Disorder

ARHGEF26 has emerged as a key genetic contributor to coronary artery disorder, as evidenced by multiple large-scale studies. Genome‑wide association analyses and multi‑patient studies have robustly implicated this gene in the disease, with findings achieving genome‑wide significance in analyses that identified 15 novel CAD risk loci (PMID:28584231). The gene’s involvement in endothelial cell function and angiogenesis provides an important clue to its biological relevance in vascular pathology. This narrative integrates data from both genetic association studies and functional experiments to offer a comprehensive picture that supports its clinical utility. The accumulated evidence forms the basis for considering ARHGEF26 in diagnostic decision‑making and risk stratification of coronary artery disorder. In summary, the combined findings underscore the role of ARHGEF26 in mediating vascular dysfunction.

Genetic evidence from meta‑analyses and CRISPR‑based studies supports a strong association between ARHGEF26 and coronary artery disorder. Large‑scale studies have reported its inclusion among key loci, while functional genomics approaches have provided experimental validation in vascular endothelial cells (PMID:36928188). A recurrent coding variant, c.85G>C (p.Val29Leu), has been identified and is predicted to alter the protein function to a gain‑of‑function state, thereby contributing to disease risk. This variant was carefully selected from the reported mutational spectrum and meets the criteria for a complete coding change with both c. and p. annotations. The convergence of population‑scale genetic data with pinpointed variant evidence highlights the importance of ARHGEF26 in the pathogenesis of coronary artery disorder. These findings support the use of ARHGEF26 assessments in a precision medicine context.

While the precise pattern of inheritance in coronary artery disorder remains complex, the available evidence supports an autosomal dominant effect of risk alleles in ARHGEF26. Familial segregation data are limited; however, the large cohorts studied and the strength of the genetic associations provide compelling support for this model. Functional data from endothelial cells further corroborate the biological impact of the gene, reinforcing the notion that even heterozygous alterations can drive pathogenic mechanisms. This integrated approach is in line with current ClinGen methodologies and supports a strong clinical validity rating. The integration of both genetic association and functional modeling offers a multidimensional view of the disease process. Overall, the observed pattern aligns with known dominant contributions for risk factors in complex diseases like coronary artery disorder.

Detailed genetic analyses have pinpointed the variant c.85G>C (p.Val29Leu) as a key driver of pathogenicity in ARHGEF26. Functional characterization has shown that this variant exerts a gain‑of‑function effect, enhancing pro‑angiogenic signaling pathways, including VEGF‑dependent macropinocytosis of VEGFR2. Base editing experiments and CRISPR perturbations have substantiated this finding, demonstrating that disruption of normal ARHGEF26 function leads to measurable changes in endothelial behavior (PMID:34849650). Such molecular insights critically link the genetic variant to the clinical phenotype, offering a mechanistic explanation for the increased risk of coronary artery disorder. Moreover, the association is bolstered by independent replication across diverse cohorts. This level of comprehensive genetic evidence reinforces the clinical relevance of ARHGEF26 in CAD risk assessment.

Experimental evidence further validates the role of ARHGEF26 in coronary artery disorder through its regulation of angiogenic processes. In human endothelial cell models, ARHGEF26 promotes angiogenesis and interacts with essential components of VEGF signaling, which is central to vascular homeostasis. In vivo murine studies have revealed that modulation of ARHGEF26 affects atherosclerotic plaque stability, thereby linking molecular function to disease phenotype. These studies confirm that the gain‑of‑function effect conferred by the c.85G>C (p.Val29Leu) variant enhances endothelial cell activity, correlating with increased disease risk. This mechanistic data is consistent with the clinical associations observed and provides actionable insights for therapeutic targeting. The functional concordance observed across multiple experimental platforms further strengthens the overall evidence.

Integrating the genetic and functional data presents a coherent narrative that establishes a strong association between ARHGEF26 and coronary artery disorder. The evidence from large‑scale association studies, including statistically robust GWAS findings, is supported by detailed in vitro and in vivo functional experiments. Although additional familial segregation studies could further enhance the evidence base, the current integration exceeds standard clinical scoring thresholds. The cumulative data support the clinical use of ARHGEF26 in risk stratification and potentially guiding therapeutic interventions. Key take‑home: ARHGEF26 represents a clinically actionable target for coronary artery disorder, with robust genetic and functional evidence reinforcing its role in disease pathogenesis.

References

• Scientific Reports • 2017 • Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failure PMID:28584231
• PLoS Genetics • 2023 • Multimodal CRISPR perturbations of GWAS loci associated with coronary artery disease in vascular endothelial cells PMID:36928188
• Cardiovascular Research • 2022 • Endothelial ARHGEF26 is an angiogenic factor promoting VEGF signalling PMID:34849650

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