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Genetic Analysis Finds Role for Insulin Resistance, Transendothelial Migration in Heart Disease

NEW YORK (GenomeWeb) – Through genetic analysis, a Harvard Medical School-led team of researchers has linked insulin resistance and an inflammatory response that occurs in atherosclerosis to coronary artery disease.

Using information housed in the UK Biobank, researchers led by Harvard's Sekar Kathiresan uncovered 15 new genetic loci associated with coronary artery disease, bringing the total number up to 95. As they reported today in Nature Genetics, the researchers' phenome-wide association studies and functional analyses of these loci highlighted a role for the insulin resistance and transendothelial migration pathways in the disease. Transendothelial migration occurs when leukocytes move across the endothelium in response to inflammation and is an initial step in atherosclerosis.

"[W]e performed a gene discovery study for [coronary artery disease] using a large population-based biobank, identified 15 new loci, and explored the phenotypic consequences of CAD risk variants through PheWAS and in vitro functional analysis," Kathiresan and his colleagues wrote in their paper.

The researchers conducted a three-stage genome-wide association study, the first stage of which searched for variants linked to coronary artery disease within 4,831 cases and 115,455 controls from the UK Biobank. They then took 2,190 variants that reached nominal significance in that stage forward to the second stage, while also taking 387,174 other variants from stage one forward to the third stage.

In the resulting meta-analysis, the researchers linked 15 new loci to coronary artery disease risk, bringing the number of known coronary artery disease risk loci to 95. They noted that one of these new loci was reported as they prepared their manuscript.

Through a phenome-wide association study using Genotype-Tissue Expression Project data, the researchers caught a glimpse into how some of these variants might influence coronary artery disease risk.

For instance, they reported that the variant rs10841443, located near PDE3A, is associated with diastolic blood pressure, and suggested that the variant could influence hypertension to increase disease risk. They likewise found that the variant rs2972146 was associated with a number of phenotypes observed in insulin resistance, such as HDL cholesterol, fasting insulin, and type 2 diabetes, among others.

However, the researchers also noted that a handful of the coronary artery disease-linked loci they uncovered weren't significantly associated with any studied known risk factor traits. Variants within FN1 and LOX, for instance, appeared to be linked to extracellular matrix biology.

A recent study found that a rare LOX coding variant seemed to cause a Mendelian form of thoracic aortic aneurysm and dissection, indicating a possible link between atherosclerosis and aortic disease, via extracellular matrix biology, the authors said.

The researchers conducted additional functional assays after one of the new loci — ARHGEF26 — couldn't be linked to known risk factors. These assays suggested that it influences the transendothelial migration of leukocytes, a key step in the development of atherosclerosis.

Knocking down ARHGEF26 in vitro led to decreased leukocyte transendothelial migration. Further, adding exogenous ARHGEF26 harboring the disease-linked variant rescued that phenotype above and beyond wild-type levels. This indicated to the researchers that this is a gain-of-function variant, and that it has a longer half-life than the wild-type protein.

"[C]onsiderable experimental evidence in cells and rodents has suggested that transendothelial migration of leukocytes is a key step in the formation of atherosclerosis; here we provide genetic support in humans for a role of this pathway in CAD," the researchers wrote.