Polygenic Background Modifies Risk of Coronary Artery Disease Among Individuals With Heterozygous Familial Hypercholesterolemia
Authors' conclusion
In 2 cohort studies involving 1,744 individuals with genetically confirmed HeFH - the largest study to date - risk of CAD varied according to polygenic background, in some cases approaching the risk observed in noncarriers.
Study context
- Population
- Individuals carrying a heterozygous familial hypercholesterolemia (HeFH) variant and matched family noncarriers from a nationwide screening programme in the Netherlands; replication in UK BiobankUK Biobank replication n = 151,009
- Participants
- 1,315 vs 1,315
- Exposure
- Polygenic score among HeFH variant carriers; HeFH carriers vs matched family noncarriers
- HeFH variant carriersn = 1,315
- Noncarriersn = 1,315reference
- Outcome
- Incident CAD by polygenic score among HeFH variant carriers
- Follow-up
- Median 10.2 years
Methodological detailsmatched family noncarriers, replication in UK Biobank
- Matched family noncarriers
- Replication in UK Biobank
Main finding
As reported in the abstract
Incident CAD per SD increase
Hazard ratio (95% CI)
Polygenic score (per SD), HeFH carriers
1.35(1.07–1.70)
LDL-C (per SD), HeFH carriers
1.41(1.17–1.70)
Per SD, as printed
- Coronary artery disease (CAD) risk vs noncarriers, lowest polygenic score quintile
- 1.24-fold (95% CI: 0.64-2.34)
- CAD risk vs noncarriers, highest polygenic score quintile
- 3.37-fold (95% CI: 2.11-5.36)
Observational data: associations, not effects.
Further findings
| Outcome | HeFH variant carriers | Noncarriers | HR (95% CI) | |
|---|---|---|---|---|
| Incident CAD, HeFH carriersvs matched family noncarriers · median follow-up 10.2 years | 6.4% | 3.4% | 1.88 (1.31–2.70) | |
| 0.20.5125Hazard ratio (log scale) |
CAD risk across polygenic score quintiles, UK Biobank carriers (replication)
- Lowest quintile vs noncarriers
- 1.36-fold (95% CI: 0.65-2.85)
- Highest quintile vs noncarriers
- 2.88-fold (95% CI: 1.59-5.20)
- 429 carriers in the UK Biobank
Original publication
Polygenic Background Modifies Risk of Coronary Artery Disease Among Individuals With Heterozygous Familial Hypercholesterolemia. JACC Adv. Published 28 October 2023. doi:10.
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