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Coronary Artery Calcification Culprits Uncovered in Sequencing-Based GWAS

NEW YORK – An international team led by investigators at Massachusetts General Hospital and other US centers has tracked down new and known genetic contributors to coronary artery calcification (CAC), a condition marked by atherosclerotic plaques that can boost heart disease risk.

"The identification of additional CAC loci could provide insights into novel pathogenic mechanisms underlying atherosclerotic cardiovascular disease," co-senior author and co-corresponding author Rajeev Malhotra, a Massachusetts General Hospital cardiologist and researcher with the MGH Cardiovascular Research Center, and his colleagues wrote in Nature Cardiovascular Research on Monday, noting that their new analyses relied on whole-genome sequencing profiles generated for the Trans-Omics for Precision Medicine (TOPMed) program.

Using whole-genome sequences and computed tomography image-based CAC measurements for 22,400 individuals enrolled through 10 prior studies, including individuals from Amish, Asian, Black, Hispanic/Latino, or White ancestry or race groups, the researchers used a genome-wide association study to search for common or rare genetic variants contributing to CAC. The findings highlighted four known loci linked to CAC and two previously unappreciated loci in and around the X chromosome gene ARSE and the chromosome 8 gene MMP16.

The GWAS "identified six genetic loci associated with CAC, a strong independent risk factor for future cardiovascular disease events," the authors reported, noting that "variants in the ARSE and MMP16 loci have not been previously reported to be associated with CAC."

The researchers went on to validate the ARSE and MMP16 associations in another 1,370 Black individuals and in nearly 1,800 individuals from a Brazilian population, since the CAC-associated ARSE SNP, known as rs5982944, appeared to be overrepresented in individuals of African ancestry.

The team's follow-up functional assays in human vascular smooth muscle cell lines originating in the coronary artery or aorta — from small interfering RNA experiments to quantitative RT-PCR measures of gene expression or immunoblot-based protein expression profiling — suggested that ARSE acts as a calcification and phenotype switching promoter in human vascular smooth muscle cells.

While the rs5982944 enhancer variant was flagged as a potential causal variant in CAC, for example, genetic variants linked to lower-than-usual expression of the gene appeared to coincide with reduced CAC risk.

Consistent with prior research that have implicated rare ARSE variants in an altered cartilage and bone development condition called X-linked chondrodysplasia punctata 1, the researcher explained, their vascular smooth muscle cell experiments suggested that ARSE regulates the transition from contractile cell features to so-called "osteogenic" features resembling those involved in bone formation.

These and other findings from the study suggested that ARSE "represents a novel locus associated with CAC that exerts direct effects on atherosclerotic vascular calcification in vitro," the authors explained, calling ARSE "a potential target of therapy for vascular calcific disease."