Rare Genetic Variants in LDLR, APOB, and PCSK9 Are Associated With Aortic Stenosis

doi:10.1161/CIRCULATIONAHA.124.070982

. 2024 Nov 26;150(22):1767-1780.

doi: 10.1161/CIRCULATIONAHA.124.070982. Epub 2024 Sep 2.

Rare Genetic Variants in LDLR, APOB, and PCSK9 Are Associated With Aortic Stenosis

Joel T Rämö^#^{1

2

3

4}, Sean J Jurgens^#^{1

2

5

6}, Shinwan Kany^#^{1

2

5

7

8}, Seung Hoan Choi⁹, Xin Wang^{1

2

10

11}, Andrey N Smirnov², Samuel F Friedman^{1

2}, Mahnaz Maddah², Shaan Khurshid^{2

5

12}, Patrick T Ellinor^#^{2

5

12

13

14}, James P Pirruccello^#^{1

2

15

16

17}

Affiliations

¹ Cardiovascular Disease Initiative (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P.), Cambridge, MA.
² Broad Institute of MIT and Harvard (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P, A.N.S., S.F.F., M.M.), Cambridge, MA.
³ Department of Medicine, Brigham and Women's Hospital, Boston, MA (J.T.R.).
⁴ Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki (J.T.R.).
⁵ Cardiovascular Research Center (J.T.R., S.J.J., S. Kany, S. Khurshid, P.T.E.), Massachusetts General Hospital, Boston.
⁶ Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam University Medical Center, University of Amsterdam, The Netherlands (S.J.J.).
⁷ Department of Cardiology, University Heart and Vascular Center Hamburg-Eppendorf, Hamburg, Germany (S. Kany).
⁸ German Center for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany (S. Kany).
⁹ Department of Biostatistics, Boston University, MA (S.H.C.).
¹⁰ Wellcome Trust Sanger Institute, Hinxton, United Kingdom (X.W.).
¹¹ University of Cambridge, United Kingdom (X.W.).
¹² Telemachus and Irene Demoulas Family Foundation Center for Cardiac Arrhythmias (S. Khurshid, P.T.E.), Massachusetts General Hospital, Boston.
¹³ Cardiology Division (P.T.E.), Massachusetts General Hospital, Boston.
¹⁴ Harvard Medical School, Boston, MA (P.T.E.).
¹⁵ Division of Cardiology (J.P.P.), University of California San Francisco.
¹⁶ Bakar Computational Health Sciences Institute (J.P.P.), University of California San Francisco.
¹⁷ Institute for Human Genetics (J.P.P.), University of California San Francisco.

^# Contributed equally.

PMID: 39222019
PMCID: PMC11915876 (available on 2025-11-26)
DOI: 10.1161/CIRCULATIONAHA.124.070982

Rare Genetic Variants in LDLR, APOB, and PCSK9 Are Associated With Aortic Stenosis

Joel T Rämö et al. Circulation. 2024.

. 2024 Nov 26;150(22):1767-1780.

doi: 10.1161/CIRCULATIONAHA.124.070982. Epub 2024 Sep 2.

Authors

Affiliations

¹ Cardiovascular Disease Initiative (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P.), Cambridge, MA.
² Broad Institute of MIT and Harvard (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P, A.N.S., S.F.F., M.M.), Cambridge, MA.
³ Department of Medicine, Brigham and Women's Hospital, Boston, MA (J.T.R.).
⁴ Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki (J.T.R.).
⁵ Cardiovascular Research Center (J.T.R., S.J.J., S. Kany, S. Khurshid, P.T.E.), Massachusetts General Hospital, Boston.
⁶ Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam University Medical Center, University of Amsterdam, The Netherlands (S.J.J.).
⁷ Department of Cardiology, University Heart and Vascular Center Hamburg-Eppendorf, Hamburg, Germany (S. Kany).
⁸ German Center for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany (S. Kany).
⁹ Department of Biostatistics, Boston University, MA (S.H.C.).
¹⁰ Wellcome Trust Sanger Institute, Hinxton, United Kingdom (X.W.).
¹¹ University of Cambridge, United Kingdom (X.W.).
¹² Telemachus and Irene Demoulas Family Foundation Center for Cardiac Arrhythmias (S. Khurshid, P.T.E.), Massachusetts General Hospital, Boston.
¹³ Cardiology Division (P.T.E.), Massachusetts General Hospital, Boston.
¹⁴ Harvard Medical School, Boston, MA (P.T.E.).
¹⁵ Division of Cardiology (J.P.P.), University of California San Francisco.
¹⁶ Bakar Computational Health Sciences Institute (J.P.P.), University of California San Francisco.
¹⁷ Institute for Human Genetics (J.P.P.), University of California San Francisco.

^# Contributed equally.

PMID: 39222019
PMCID: PMC11915876 (available on 2025-11-26)
DOI: 10.1161/CIRCULATIONAHA.124.070982

Abstract

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.

Keywords: aortic valve stenosis; cholesterol; genetics; lipids; lipoproteins, LDL; magnetic resonance imaging; receptors, LDL.

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Conflict of interest statement

Dr Ellinor receives sponsored research support from Bayer AG, IBM Research, Bristol Myers Squibb, Pfizer, and Novo Nordisk; he has also served on advisory boards or consulted for Bayer AG. The other authors report no conflicts.

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References

1. Martinsson A, Li X, Andersson C, Nilsson J, Smith JG, Sundquist K. Temporal trends in the incidence and prognosis of aortic stenosis: a nationwide study of the Swedish population. Circulation. 2015;131:988–994. - PubMed
1. Lancellotti P, Magne J, Dulgheru R, Clavel M-A, Donal E, Vannan MA, Chambers J, Rosenhek R, Habib G, Lloyd G, et al. Outcomes of Patients With Asymptomatic Aortic Stenosis Followed Up in Heart Valve Clinics. JAMA Cardiol. 2018;3:1060–1068. - PMC - PubMed
1. Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J. Am. Coll. Cardiol. 1997;29:630–634. - PubMed
1. Yan AT, Koh M, Chan KK, Guo H, Alter DA, Austin PC, Tu JV, Wijeysundera HC, Ko DT. Association Between Cardiovascular Risk Factors and Aortic Stenosis: The CANHEART Aortic Stenosis Study. J. Am. Coll. Cardiol. 2017;69:1523–1532. - PubMed
1. Ten Kate G-JR, Bos S, Dedic A, Neefjes LA, Kurata A, Langendonk JG, Liem A, Moelker A, Krestin GP, de Feyter PJ, et al. Increased Aortic Valve Calcification in Familial Hypercholesterolemia: Prevalence, Extent, and Associated Risk Factors. J. Am. Coll. Cardiol. 2015;66:2687–2695. - PubMed

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[1] Martinsson A, Li X, Andersson C, Nilsson J, Smith JG, Sundquist K. Temporal trends in the incidence and prognosis of aortic stenosis: a nationwide study of the Swedish population. Circulation. 2015;131:988–994. - PubMed

[2] Martinsson A, Li X, Andersson C, Nilsson J, Smith JG, Sundquist K. Temporal trends in the incidence and prognosis of aortic stenosis: a nationwide study of the Swedish population. Circulation. 2015;131:988–994. - PubMed

[3] Lancellotti P, Magne J, Dulgheru R, Clavel M-A, Donal E, Vannan MA, Chambers J, Rosenhek R, Habib G, Lloyd G, et al. Outcomes of Patients With Asymptomatic Aortic Stenosis Followed Up in Heart Valve Clinics. JAMA Cardiol. 2018;3:1060–1068. - PMC - PubMed

[4] Lancellotti P, Magne J, Dulgheru R, Clavel M-A, Donal E, Vannan MA, Chambers J, Rosenhek R, Habib G, Lloyd G, et al. Outcomes of Patients With Asymptomatic Aortic Stenosis Followed Up in Heart Valve Clinics. JAMA Cardiol. 2018;3:1060–1068. - PMC - PubMed

[5] Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J. Am. Coll. Cardiol. 1997;29:630–634. - PubMed

[6] Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J. Am. Coll. Cardiol. 1997;29:630–634. - PubMed

[7] Yan AT, Koh M, Chan KK, Guo H, Alter DA, Austin PC, Tu JV, Wijeysundera HC, Ko DT. Association Between Cardiovascular Risk Factors and Aortic Stenosis: The CANHEART Aortic Stenosis Study. J. Am. Coll. Cardiol. 2017;69:1523–1532. - PubMed

[8] Yan AT, Koh M, Chan KK, Guo H, Alter DA, Austin PC, Tu JV, Wijeysundera HC, Ko DT. Association Between Cardiovascular Risk Factors and Aortic Stenosis: The CANHEART Aortic Stenosis Study. J. Am. Coll. Cardiol. 2017;69:1523–1532. - PubMed

[9] Ten Kate G-JR, Bos S, Dedic A, Neefjes LA, Kurata A, Langendonk JG, Liem A, Moelker A, Krestin GP, de Feyter PJ, et al. Increased Aortic Valve Calcification in Familial Hypercholesterolemia: Prevalence, Extent, and Associated Risk Factors. J. Am. Coll. Cardiol. 2015;66:2687–2695. - PubMed

[10] Ten Kate G-JR, Bos S, Dedic A, Neefjes LA, Kurata A, Langendonk JG, Liem A, Moelker A, Krestin GP, de Feyter PJ, et al. Increased Aortic Valve Calcification in Familial Hypercholesterolemia: Prevalence, Extent, and Associated Risk Factors. J. Am. Coll. Cardiol. 2015;66:2687–2695. - PubMed

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Rare Genetic Variants in LDLR, APOB, and PCSK9 Are Associated With Aortic Stenosis

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Rare Genetic Variants in LDLR, APOB, and PCSK9 Are Associated With Aortic Stenosis

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