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Rare Genetic Variants in LDLR, APOB, and PCSK9 Are Associated With Aortic Stenosis
Joel T Rämö1,2,3,4, Sean J Jurgens1,2,5,6, Shinwan Kany1,2,5,7,8
1Cardiovascular Disease Initiative (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P.), Cambridge, MA.
Insights
Lifelong high LDL-C from genetic variants significantly increases aortic stenosis risk, while lifelong low LDL-C decreases it. Early lipid-lowering therapy may prevent or slow AS development.
Area of Science:
- Cardiovascular Genetics
- Metabolic Disease Research
- Aortic Valve Disease
Background:
- Aortic stenosis (AS) is linked to LDL-C, but trials of lipid-lowering drugs have not prevented severe AS.
- Investigated lifelong LDL-C alterations from genetic variants in LDLR, APOB, and PCSK9 genes.
Purpose of the Study:
- To assess the impact of lifelong LDL-C changes on AS and aortic valve peak velocity.
- Examined protein-disrupting variants in LDL metabolism genes.
Main Methods:
- Utilized UK Biobank and All of Us data, including sequencing, electronic health records, and MRI.
- Identified variants using LOFTEE and AlphaMissense algorithms.
- Evaluated associations with LDL-C, AS, aortic valve replacement, and peak velocity.
Main Results:
- Carriers of LDLR variants had higher LDL-C, increased AS risk (OR 3.52), and aortic valve replacement risk (OR 3.78).
- Carriers of APOB or PCSK9 variants had lower LDL-C, decreased AS risk (OR 0.49), and aortic valve replacement risk (OR 0.54).
- LDLR variant carriers showed higher aortic valve peak velocity, while PCSK9 variant carriers showed lower velocity.
Conclusions:
- Rare genetic variants causing lifelong high or low LDL-C are linked to substantially increased or decreased AS risk, respectively.
- Suggests early and sustained lipid-lowering therapy could slow or prevent AS development.
Background:
Despite a proposed causal role for LDL-C (low-density lipoprotein cholesterol) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in 3 clinically significant genes for LDL (low-density lipoprotein) metabolism (LDLR, APOB, and PCSK9).
Methods:
We used sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the Loss Of Function Transcript Effect Estimator (LOFTEE) and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank and All of Us).
Results:
We included 421 049 unrelated participants (5621 with AS) in UKB and 195 519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in LDLR had higher mean LDL-C (UKB: +42.6 mg/dL; P=4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39-5.20]; P=2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26-6.32]; P=4.0e-7). Carriers of protein-disrupting variants in APOB or PCSK9 had lower mean LDL-C (UKB: -32.3 mg/dL; P<5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31-0.75]; P=0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30-0.97]; P=0.04). Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in LDLR (+12.2 cm/s; P=1.6e-5) and lower in carriers of protein-disrupting variants in PCSK9 (-6.9 cm/s; P=0.022).
Conclusions:
Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development.
