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Newly Identified Genes Linked to Coronary Artery Calcification

Key findings

  • This paper reports on a multi-ancestry genome-wide association study meta-analysis of coronary artery calcification (CAC), the largest ever conducted (26,909 individuals of European ancestry and 8,867 individuals of African ancestry)
  • The team identified 43 candidate genes linked to CAC at 11 genomic loci, including eight loci not previously connected to CAC; the novel loci were related to bone mineralization, vitamin and phosphate metabolism, and hormone secretion pathways
  • Five of the novel loci (ENPP1/ENPP3, IGFBP3, ARID5B, ADK, and FGF23) have not been previously linked to coronary artery disease, but IGFBP3, ARID5B, and ADK proved to have a key role in promoting vascular smooth muscle cell calcification
  • Many of the CAC-associated genes encode proteins that are targets of approved drugs, supplements, or investigational compounds
  • These newly identified genetic risk factors for CAC may lead to development of new drugs, or the identification of existing drugs, for the prevention of coronary artery disease

Coronary artery calcification (CAC), as measured with cardiac computed tomography, is a reliable measure of subclinical atherosclerosis and predicts future symptomatic coronary artery disease (CAD). The estimated heritability for CAC is 30% to 40%, but until recently, only four genetic loci for CAC had been identified in genome-wide association studies (GWAS) in the general population.

Hanna J. Barnes, MD, a clinical fellow at Brigham and Women's Hospital, Christian L. Lino Cardenas, PhD, PharmD, an instructor in medicine in the Cardiovascular Research Center at Massachusetts General Hospital, Rajeev Malhotra, MD, a cardiologist and principal investigator in the Cardiovascular Research Center at Mass General and associate professor at Harvard Medical School, and an international team of colleagues recently completed the largest multi-ancestry GWAS meta-analysis of CAC to date. It comprised 16 cohorts that contributed 26,909 individuals exclusively of European ancestry and 8,867 individuals of African ancestry. In Nature Genetics, the team reports findings that may point to new therapeutic strategies for preventing CAD.

Novel Genomic Loci

The researchers identified 16 independent genome-wide significant variant associations for CAC at 11 distinct genomic loci. These included eight loci not previously reported to be associated with CAC. The novel loci were found to be associated with bone mineralization regulation, vitamin D receptor, riboflavin metabolism, phosphate catabolism/homeostasis, and hormone secretion pathways.

By integrating functional data with GWAS results and gene-based analyses, the team identified 43 total candidate genes for CAC.

Functional Validation

Five of the novel loci (ENPP1/ENPP3, IGFBP3, ARID5B, ADK, and FGF23) have not been previously reported in association with CAC. In vitro, functional validation of ENPP1, IGFBP3, ARID5B, and ADK supported a causal role for them in CAC. Specifically, IGFBP3, ARID5B, and ADK were shown to play a key role in promoting vascular smooth muscle cell calcification, whereas ENPP1 inhibits calcification.

Druggability Analyses

Many of the CAC-associated genes were found to encode proteins identified as predicted targets of approved drugs, supplements or investigational compounds. This suggests opportunities to study whether those compounds—and possibly even dietary changes—could be early interventions to prevent CAD.

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