Polygenic Background Modifies Risk of Coronary Artery Disease Among Individuals With Heterozygous...

Area of Science:

• Genetics
• Cardiovascular Medicine
• Molecular Biology

Background:

• Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder causing high LDL cholesterol and early atherosclerosis.
• Significant variability in coronary artery disease (CAD) risk exists even among individuals with HeFH.

Purpose of the Study:

• To assess the combined effect of common DNA variations, measured by a polygenic score, on the development of CAD in individuals with HeFH.
• To understand how genetic background influences CAD risk in the context of a known HeFH-causing variant.

Main Methods:

• Analysis of a prospective cohort of 1,315 individuals with HeFH variants and 1,315 matched noncarriers from the Netherlands.
• Replication analysis in 151,009 participants from the UK Biobank.
• Calculation of polygenic scores to quantify the cumulative impact of common DNA variants.

Main Results:

• HeFH carriers had a higher incidence of CAD (6.4%) compared to noncarriers (3.4%) over a median follow-up of 10.2 years (HR 1.88).
• In HeFH carriers, polygenic score was significantly associated with CAD risk (HR 1.35 per SD increase), comparable to LDL cholesterol's effect.
• CAD risk in HeFH carriers increased substantially with higher polygenic score quintiles, ranging from 1.24-fold to 3.37-fold compared to noncarriers.

Conclusions:

• This study, the largest to date on genetically confirmed HeFH, demonstrates that CAD risk varies based on an individual's polygenic background.
• In some cases, the polygenic background can mitigate CAD risk in HeFH patients, bringing it closer to that of noncarriers.