Genetic-Phenotypic Discordance Reveals Distinct Cardiovascular and Mortality Risk at HDL Cholesterol Extremes
Elad Shemesh, Keona Pang, Pascal B. Meyre, Alice Man, Josef Graf, Shuang Wang, YanRan Li, Pierre Beaucage, Guilherme Luiz Da Rocha, Michael Kamal, Marie Pigeyre, Michael D. Shapiro, Guillaume ParéBACKGROUND:
Risk at high-density lipoprotein cholesterol (HDL-C) extremes may reflect genetic predisposition, ancestry, or region, but their relative contributions remain unknown. We characterized extreme HDL-C associations with atherosclerotic cardiovascular disease and mortality, and examined whether genetic-phenotypic discordance identifies risk beyond measured HDL-C.
METHODS:
Atherosclerotic cardiovascular disease–free participants from UKB (UK Biobank) and All of Us (AoU) with extremely low (<1 mmol/L) or extremely high (>2.3 mmol/L; based on standard clinical guidelines) HDL-C were analyzed. A 247-variant polygenic score stratified European ancestry participants at each HDL-C extreme into tertiles; discordant groups had measured HDL-C contradicting genetic predisposition.
RESULTS:
Among 408 353 UKB and 115 423 AoU participants, extremely low HDL-C was associated with higher atherosclerotic cardiovascular disease (UKB: hazard ratio [HR], 1.33 [95% CI, 1.27–1.39]; AoU: HR, 1.32 [95% CI, 1.08–1.61]) and mortality (UKB: HR, 1.25 [95% CI, 1.20–1.30]; AoU: HR, 1.64 [95% CI, 1.37–1.96]) across ancestries. Extremely high HDL-C was associated with excess mortality in UKB European ancestry (HR, 1.28 [95% CI, 1.19–1.38]), driven by COPD (HR, 2.64 [1.94–3.59]) and lung infections (HR, 2.24 [95% CI, 1.48–3.39]), but not in AoU European ancestry. In UKB, this was confined to genetically discordant high HDL (high-density lipoprotein; polygenic score HDL T1; HR, 1.53 [95% CI, 1.22–1.92]); genetically concordant high HDL showed progressively lower mortality. Genetically discordant low HDL (polygenic score HDL T3) carried higher atherosclerotic cardiovascular disease (UKB: HR, 1.20 [95% CI, 1.08–1.34]; AoU: HR, 1.44 [95% CI, 1.15–1.81]) and mortality (UKB: HR, 1.22 [95% CI, 1.11–1.34]; AoU: HR, 1.75 [95% CI, 1.21–2.54]) than concordant low HDL (polygenic score HDL T1), comparable in magnitude to a 10 mm Hg increment in systolic blood pressure.
CONCLUSIONS:
Extreme HDL-C levels carry different cardiovascular and mortality risk depending on whether they reflect or contradict genetic predisposition, with additional variation by ancestry and region.