20th Annual Sleep and Health Benefit

Pathway-specific Polygenic Risk Scores (PGRS) identify CVD pathways moderated by OSA

Matthew Goodman, MS, PhD

Brigham and Women's Hospital, Harvard Medical School

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Clinical Implications
Obstructive sleep apnea may moderate genetic risk of CAD selectively in genetic regulatory pathways related to intermittent hypoxia and interrupted sleep, with qualitative risk-increasing and risk-decreasing effect-measure modification of inherited genetic risk risk.
Research Narrative

Obstructive sleep apnea (OSA) is a common breathing disorder characterized by recurrent episodes of upper airway collapse with reduced airflow, oxygen desaturation and consequent intermittent hypoxia, as well as sleep disruption, which are implicated in increased risk of cardiovascular disease. Surprisingly, although there is a strong dose-response association between OSA and stroke, evidence of a link between OSA and coronary artery disease (CAD) is less certain. One possibility is that OSA is a “double-edged sword” with some positive as well as negative consequences for CAD event risk. At certain doses, intermittent hypoxia (IH) may reduce CAD event risk by ischemic preconditioning, with positive effects on angiogenesis, coronary collateralization and increased antioxidant production. By contrast, IH may increase CAD event risk via oxidative stress and inflammation. Simulataneously, sleep disruption can have effects on immune differentiation and signalling. We find evidence that pathway-specific genetic risk of CAD differs when comparing individuals with and without OSA. Elevated PS-PGRSs for the HIF-1 and Hematopoietic cell lineage pathways are nominally associated with excess risk of CAD in OSA, but elevated PS-PGRSs for the MAPK and VEGF pathways are associated with protection for CAD in OSA. The effect size of this pathway-dependent qualitative effect modification is large enough to multiply or cancel the estimated CAD effect due to OSA itself. This provides evidence that gene-by-environment interaction may play an appreciable role in understanding CAD risk in people with OSA.

Research Category
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