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Polygenic SNP Score Correlates With Early-Onset Coronary Artery Disease Risk

NEW YORK (GenomeWeb) – A polygenic risk score comprised of almost 200 common variants may help to foretell an individual's risk of being diagnosed with coronary artery disease at a relatively young age, according to new research.

As they reported in the journal Circulation: Cardiovascular Genetics, researchers from McMaster University, the Population Health Research Institute (PHRI), and Laval University searched genotyping profiles for more than 111,000 UK Biobank participants for 182 common variants associated with coronary artery disease and calculated a polygenic risk score (GRS182) based on their presence.

The team noted that higher risk scores were associated with early-onset coronary artery disease (EOCAD) in a manner that was roughly comparable to independent risk factors, such as familial hypercholesterolemia scores — results that were subsequently supported by testing in an independent group of 30 individuals treated for EOCAD at a Hamilton, Ontario clinic from early 2014 through the spring of 2016.

"The increase in genetic risk was independent of other known risk factors, suggesting that testing for multiple genetic differences is clinically useful to evaluate risk and guide management," corresponding author Guillaume Paré, a pathology and molecular medicine researcher affiliated with McMaster University and PHRI, said in a statement. "Combining polygenic screening with current testing for familial hypercholesterolemia could potentially increase fivefold the number of cases for which a genetic explanation can be found."

Coronary artery disease risk can vary depending on lifestyle factors such as smoking, diet, and physical activity, the team explained. But genetic contributors may also impact EOCAD risk — coronary disease onset prior to the age of 40 in men or 45 in women. In familial hypercholesterolemia, for example, a Mendelian condition, a genetic glitch impacts blood levels of risky low-density lipoprotein cholesterol levels.

"Despite evidence of high heritability, monogenic disorders are identified in a minor fraction of individuals with [EOCAD]," the authors wrote. "We hypothesized that some individuals with EOCAD carry a high number of common genetic risk variants."

To search for such broader EOCAD contributors, the researchers analyzed directly assessed and imputed SNPs in nearly 111,400 UK Biobank participants previously genotyped on Affymetrix arrays, including 96 EOCAD-affected individuals who underwent a revascularization procedure and 111,283 unaffected controls.

One of every 53 individuals had a high GRS182 score with an effect that on par with that of familial hypercholesterolemia.

In a validation cohort comprised of 30 individuals with EOCAD, meanwhile, the team saw an overall uptick in GRS182 scores, uncovering seven individuals with GRS182 scores that were roughly twice as high as those found in unaffected individuals from the UK Biobank project.

"Our results provide convincing evidence that the polygenic risk score could be added to the genetic investigation of patients with very early coronary artery disease," first author Sébastien Thériault, a researcher affiliated with McMaster, the PHRI, and Laval University's Quebec Heart and Lung Institute Research Center, said in a statement. 

The researchers noted that the results so far apply to individuals of European ancestry, meaning the GRS182 will have to be assessed in additional population groups. Likewise, the "pathophysiological mechanism" of the described risk SNP set remains unknown, they noted, though the GRS182 score itself appears to have potential for informing EOCAD risk beyond factors described in the past.