Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study
Open accessAbstract
Aims: Aortic valve stenosis is commonly considered a degenerative disorder with no recommended preventive intervention, with only valve replacement surgery or catheter intervention as treatment options. We sought to assess the causal association between exposure to lipid levels and risk of aortic stenosis. Methods and results: Causality of association was assessed using two-sample Mendelian randomization framework through different statistical methods. We retrieved summary estimations of 157 genetic variants that have been shown to be associated with plasma lipid levels in the Global Lipids Genetics Consortium that included 188 577 participants, mostly European ancestry, and genetic association with aortic stenosis as the main outcome from a total of 432 173 participants in the UK Biobank. Secondary negative control outcomes included aortic regurgitation and mitral regurgitation. The odds ratio for developing aortic stenosis per unit increase in lipid parameter was 1.52 [95% confidence interval (CI) 1.22–1.90; per 0.98 mmol/L] for low density lipoprotein (LDL)-cholesterol, 1.03 (95% CI 0.80–1.31; per 0.41 mmol/L) for high density lipoprotein (HDL)-cholesterol, and 1.38 (95% CI 0.92–2.07; per 1 mmol/L) for triglycerides. There was no evidence of a causal association between any of the lipid parameters and aortic or mitral regurgitation. Conclusion: Lifelong exposure to high LDL-cholesterol increases the risk of symptomatic aortic stenosis, suggesting that LDL-lowering treatment may be effective in its prevention.
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Robust translational data suggest that apolipoprotein B-containing lipoproteins, including Lp(a), are causal for aortic stenosis.
“This result is concordant with robust translational data suggesting that apolipoprotein B-containing lipoproteins, including Lp(a), are causal for AS7,37,38.”
From Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction (2026) · cites this paper as [37]
Previous Mendelian randomization studies aggregating common genetic variants estimated that a 38.67 mg/dL (1 mmol/L) lower LDL-C was associated with 12% to 45% lower odds or hazards of AS.
“Causal effect estimates from these studies, converted to risk reductions, have ranged between 12% and 45% lower odds or hazards of AS per 38.67-mg/ dL (1-mmol/L) reduction in LDL-C.7,[9][10][11]”
From Rare Genetic Variants in <i>LDLR</i> , <i>APOB</i> , and <i>PCSK9</i> Are Associated With Aortic Stenosis (2024) · cites this paper as [10]
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Cites
Sudlow, C., Gallacher, J., Allen, N., Beral, V., Burton, P., Danesh, J., Downey, P., Elliott, P., Green, J., Landray, M., et al. (2015) · PLOS Medicine · doi:10.1371/journal.pmed.1001779 · Cited by 12,728 · see citing works
Bowden, J., Davey Smith, G., & Burgess, S. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyv080 · Cited by 9,816 · see citing works
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz455 · Cited by 8,961 · see citing works
Bowden, J., Davey Smith, G., Haycock, P. C., & Burgess, S. (2016) · Genetic Epidemiology · doi:10.1002/gepi.21965 · Cited by 8,922 · see citing works
The UK Biobank resource with deep phenotyping and genomic data
Bycroft, C., Freeman, C., Petkova, D., Band, G., Elliott, L. T., Sharp, K., Motyer, A., Vukcevic, D., Delaneau, O., O’Connell, J., et al. (2018) · Nature · doi:10.1038/s41586-018-0579-z · Cited by 8,876 · see citing works
Verbanck, M., Chen, C.-Y., Neale, B., & Do, R. (2018) · Nature Genetics · doi:10.1038/s41588-018-0099-7 · Cited by 8,591 · see citing works
The MR-Base platform supports systematic causal inference across the human phenome
Hemani, G., Zheng, J., Elsworth, B., Wade, K. H., Haberland, V., Baird, D., Laurin, C., Burgess, S., Bowden, J., Langdon, R., et al. (2018) · eLife · doi:10.7554/elife.34408 · Cited by 7,959 · see citing works
2017 ESC/EACTS Guidelines for the management of valvular heart disease
Baumgartner, H., Falk, V., Bax, J. J., Bonis, M. D., Hamm, C. W., Holm, P. J., Iung, B., Lancellotti, P., Lansac, E., Muñoz, D. R., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx391 · Cited by 6,273 · see citing works
Davey Smith, G., & Ebrahim, S. (2003) · International Journal of Epidemiology · doi:10.1093/ije/dyg070 · Cited by 5,882 · see citing works
Burden of valvular heart diseases: a population-based study
Nkomo, V. T., Gardin, J. M., Skelton, T. N., Gottdiener, J. S., Scott, C. G., & Enriquez-Sarano, M. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69208-8 · Cited by 4,881 · see citing works
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.08.014 · Cited by 4,854 · see citing works
Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption
Hartwig, F. P., Davey Smith, G., & Bowden, J. (2017) · International Journal of Epidemiology · doi:10.1093/ije/dyx102 · Cited by 3,485 · see citing works
Willer (2013) · doi:10.1038/ng.2797 · Cited by 2,983 · see citing works
Clinical Factors Associated With Calcific Aortic Valve Disease
Stewart, B. F., Siscovick, D., Lind, B. K., Gardin, J. M., Gottdiener, J. S., Smith, V. E., Kitzman, D. W., & Otto, C. M. (1997) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(96)00563-3 · Cited by 2,029 · see citing works
Self-citationEffects of dalcetrapib in patients with a recent acute coronary syndrome
Schwartz, G. G., Olsson, A. G., Abt, M., Ballantyne, C. M., Barter, P. J., Brumm, J., Chaitman, B. R., Holme, I. M., Kallend, D., Leiter, L. A., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1206797 · Cited by 2,022 · see citing works
Burgess, S., Bowden, J., Fall, T., Ingelsson, E., & Thompson, S. G. (2017) · Epidemiology · doi:10.1097/ede.0000000000000559 · Cited by 2,017 · see citing works
Yavorska, O. O., & Burgess, S. (2017) · International Journal of Epidemiology · doi:10.1093/ije/dyx034 · Cited by 2,013 · see citing works
Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
Cardiogenics, Schunkert, H., the CARDIoGRAM Consortium, König, I. R., Kathiresan, S., Reilly, M. P., Assimes, T. L., Holm, H., Preuss, M., Stewart, A. F. R., et al. (2011) · Nature Genetics · doi:10.1038/ng.784 · Cited by 1,866 · see citing works
Self-citationCalculating statistical power in Mendelian randomization studies.
Brion, M.-J. A., Shakhbazov, K., & Visscher, P. M. (2013) · International Journal of Epidemiology · doi:10.1093/ije/dyt179 · Cited by 1,751 · see citing works
Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis
Rossebø, A. B., Pedersen, T. R., Boman, K., Brudi, P., Chambers, J. B., Egstrup, K., Gerdts, E., Gohlke-Bärwolf, C., Holme, I., Kesäniemi, Y. A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0804602 · Cited by 1,644 · see citing works
Burgess, S., & Thompson, S. G. (2015) · American Journal of Epidemiology · doi:10.1093/aje/kwu283 · Cited by 1,605 · see citing works
Sarwar, N., Danesh, J., Eiriksdottir, G., Sigurdsson, G., Wareham, N., Bingham, S., Boekholdt, S. M., Khaw, K.-T., & Gudnason, V. (2007) · Circulation · doi:10.1161/circulationaha.106.637793 · Cited by 1,408 · see citing works
Otto, C. M., Kuusisto, J., Reichenbach, D. D., Gown, A. M., & O’Brien, K. D. (1994) · Circulation · doi:10.1161/01.cir.90.2.844 · Cited by 1,315 · see citing works
Self-citationGlobal, Regional, and National Burden of Rheumatic Heart Disease, 1990–2015
Watkins, D., Johnson, C. O., Colquhoun, S., Karthikeyan, G., Beaton, A., Bukhman, G., Forouzanfar, M. H., Longenecker, C. T., Mayosi, B. M., Mensah, G. A., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1603693 · Cited by 1,235 · see citing works
A Randomized Trial of Intensive Lipid-Lowering Therapy in Calcific Aortic Stenosis
Cowell, S. J., Newby, D. E., Prescott, R. J., Bloomfield, P., Reid, J., Northridge, D. B., & Boon, N. A. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043876 · Cited by 1,146 · see citing works
Sanderson, E., Davey Smith, G., Windmeijer, F., & Bowden, J. (2019) · International Journal of Epidemiology · doi:10.1093/ije/dyy262 · Cited by 1,085 · see citing works
Genetic Associations with Valvular Calcification and Aortic Stenosis
Thanassoulis, G., Campbell, C. Y., Owens, D. S., Smith, J. G., Smith, A. V., Peloso, G. M., Kerr, K. F., Pechlivanis, S., Budoff, M. J., Harris, T. B., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109034 · Cited by 1,008 · see citing works
Burgess, S., Dudbridge, F., & Thompson, S. G. (2015) · American Journal of Epidemiology · doi:10.1093/aje/kwv017 · Cited by 945 · see citing works
Hartwig, F. P., Davies, N. M., Hemani, G., & Davey Smith, G. (2016) · International Journal of Epidemiology · doi:10.1093/ije/dyx028 · Cited by 860 · see citing works
Chan, K. L., Teo, K., Dumesnil, J. G., Ni, A., & Tam, J. (2010) · Circulation · doi:10.1161/circulationaha.109.900027 · Cited by 815 · see citing works
Commentary: Two-sample Mendelian randomization: opportunities and challenges
Lawlor, D. A. (2016) · International Journal of Epidemiology · doi:10.1093/ije/dyw127 · Cited by 810 · see citing works
Evacetrapib and cardiovascular outcomes in high-risk vascular disease
Lincoff, A. M., Nicholls, S. J., Riesmeyer, J. S., Barter, P. J., Brewer, H. B., Fox, K. A. A., Gibson, C. M., Granger, C., Menon, V., Montalescot, G., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1609581 · Cited by 801 · see citing works
Ference, B. A., Kastelein, J. J. P., Ray, K. K., Ginsberg, H. N., Chapman, M. J., Packard, C. J., Laufs, U., Oliver-Williams, C., Wood, A. M., Butterworth, A. S., et al. (2019) · JAMA · doi:10.1001/jama.2018.20045 · Cited by 724 · see citing works
O’Brien, K. D., Reichenbach, D. D., Marcovina, S. M., Kuusisto, J., Alpers, C. E., & Otto, C. M. (1996) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.16.4.523 · Cited by 560 · see citing works
Self-citationMethodological Challenges in Mendelian Randomization
VanderWeele, T. J., Tchetgen Tchetgen, E. J., Cornelis, M., & Kraft, P. (2014) · Epidemiology · doi:10.1097/ede.0000000000000081 · Cited by 555 · see citing works
Statin therapy increases lipoprotein(a) levels
Tsimikas, S., Gordts, P. L. S. M., Nora, C., Yeang, C., & Witztum, J. L. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz310 · Cited by 512 · see citing works
Presence of Oxidized Low Density Lipoprotein in Nonrheumatic Stenotic Aortic Valves
Olsson, M., Thyberg, J., & Nilsson, J. (1999) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.19.5.1218 · Cited by 417 · see citing works
Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study
Andell, P., Li, X., Martinsson, A., Andersson, C., Stagmo, M., Zöller, B., Sundquist, K., & Smith, J. G. (2017) · Heart · doi:10.1136/heartjnl-2016-310894 · Cited by 348 · see citing works
The modern epidemiology of heart valve disease
Coffey, S., Cairns, B. J., & Iung, B. (2015) · Heart · doi:10.1136/heartjnl-2014-307020 · Cited by 326 · see citing works
Association of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes
White, J., Swerdlow, D. I., Preiss, D., Fairhurst-Hunter, Z., Keating, B. J., Asselbergs, F. W., Sattar, N., Humphries, S. E., Hingorani, A. D., & Holmes, M. V. (2016) · JAMA Cardiology · doi:10.1001/jamacardio.2016.1884 · Cited by 293 · see citing works
Association Between Cardiovascular Risk Factors and Aortic Stenosis
Yan, A. T., Koh, M., Chan, K. K., Guo, H., Alter, D. A., Austin, P. C., Tu, J. V., Wijeysundera, H. C., & Ko, D. T. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.01.025 · Cited by 247 · see citing works
Smith, J. G., Luk, K., Schulz, C.-A., Engert, J. C., Do, R., Hindy, G., Rukh, G., Dufresne, L., Almgren, P., Owens, D. S., et al. (2014) · JAMA · doi:10.1001/jama.2014.13959 · Cited by 238 · see citing works
Qi, G., & Chatterjee, N. (2019) · Nature Communications · doi:10.1038/s41467-019-09432-2 · Cited by 207 · see citing works
Calcific aortic valve stenosis: hard disease in the heart
Peeters, F. E. C. M., Meex, S. J. R., Dweck, M. R., Aïkawa, E., Crijns, H. J. G. M., Schurgers, L. J., & Kietselaer, B. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx653 · Cited by 200 · see citing works
Taylor, A. E., Davies, N. M., Ware, J. J., VanderWeele, T., Smith, G. D., & Munafò, M. R. (2014) · Economics & Human Biology · doi:10.1016/j.ehb.2013.12.002 · Cited by 166 · see citing works
Self-citationInterpretation and Potential Biases of Mendelian Randomization Estimates With Time-Varying Exposures
Labrecque, J. A., & Swanson, S. A. (2019) · American Journal of Epidemiology · doi:10.1093/aje/kwy204 · Cited by 139 · see citing works
Dichtl, W., Alber, H. F., Feuchtner, G. M., Hintringer, F., Reinthaler, M., Bartel, T., Süssenbacher, A., Grander, W., Ulmer, H., Pachinger, O., et al. (2008) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2008.04.060 · Cited by 108 · see citing works
Systolic Blood Pressure and Risk of Valvular Heart Disease
Nazarzadeh, M., Pinho‐Gomes, A., Smith-Byrne, K., Canoy, D., Raimondi, F. E. D., Solares, J. R. A., Otto, C. M., & Rahimi, K. (2019) · JAMA Cardiology · doi:10.1001/jamacardio.2019.2202 · Cited by 108 · see citing works
Self-citationFairbairn, T. A., Meads, D. M., Hulme, C. T., Mather, A. N., Plein, S., Blackman, D. J., & Greenwood, J. P. (2013) · Heart · doi:10.1136/heartjnl-2013-303722 · Cited by 96 · see citing works
Nonrheumatic calcific aortic stenosis: an overview from basic science to pharmacological prevention☆
Parolari, A., Loardi, C. M., Mussoni, L., Cavallotti, L., Camera, M., Biglioli, P., Tremoli, E., & Alamanni, F. (2009) · European Journal of Cardio-Thoracic Surgery · doi:10.1016/j.ejcts.2008.11.033 · Cited by 77 · see citing works
Atherosclerosis-like lesions of the aortic valve are common in adults of all ages: a necropsy study
Kuusisto, J., Räsänen, K., Särkioja, T., Alarakkola, E., & Kosma, V.-M. (2005) · Heart · doi:10.1136/hrt.2004.036848 · Cited by 40 · see citing works
Gebhard, C., Maafi, F., Stähli, B. E., Bonnefoy, A., Gebhard, C. E., Nachar, W., Moraes, A. B. D. O., Mecteau, M., Mihalache-Avram, T., Lavoie, V., et al. (2018) · Thrombosis and Haemostasis · doi:10.1160/th17-10-0729 · Cited by 6 · see citing works
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Calcific aortic valve disease: mechanisms, prevention and treatment
Moncla, L.-H. M., Briend, M., Bossé, Y., & Mathieu, P. (2023) · Nature Reviews Cardiology · doi:10.1038/s41569-023-00845-7 · Cited by 319 · see citing works
Small, A. M., Peloso, G. M., Linefsky, J., Aragam, J., Galloway, A., Tanukonda, V., Wang, L.-C., Yu, Z., Sunitha Selvaraj, M., Farber-Eger, E. H., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.061451 · Cited by 76 · see citing works
Lee, S. H., Kim, N., Kim, M., Woo, S.-H., Han, I., Park, J., Kim, K., Park, K. S., Kim, K., Shim, D., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33202-2 · Cited by 70 · see citing works
Thériault, S., Li, Z., Abner, E., Luan, J., Manikpurage, H. D., Houessou, U., Zamani, P., Briend, M., Estonian Biobank Research Team, Boudreau, D. K., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46639-4 · Cited by 49 · see citing works
Rämö, J. T., Jurgens, S. J., Kany, S., Choi, S. H., Wang, X., Smirnov, A. N., Friedman, S. F., Maddah, M., Khurshid, S., Ellinor, P. T., et al. (2024) · Circulation · doi:10.1161/circulationaha.124.070982 · Cited by 26 · see citing works
Siudut, J., Natorska, J., Wypasek, E., Wiewiórka, Ł., Ostrowska-Kaim, E., Wiśniowska-Śmiałek, S., Plens, K., Musialek, P., Legutko, J., & Undas, A. (2022) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2022.01.011 · Cited by 16 · see citing works
Small, A. M., Yang, T.-Y., Itoh, S., Thériault, S., Dufresne, L., Kurosawa, R., Komuro, I., Matsuda, K., Vy, H. M. T., Farber-Eger, E. H., et al. (2026) · Nature Genetics · doi:10.1038/s41588-025-02417-6 · Cited by 12 · see citing works
“This result is concord-ant with robust translational data suggesting that apolipoprotein B-containing lipoproteins, including Lp(a), are causal for AS 7,37,38 .”
Yang, L., Xu, M., Gao, X., Liu, J., Zhang, D., Zhang, Z., Ye, Z., Wen, J., & Liu, P. (2024) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm2508292 · Cited by 6 · see citing works
“However, randomized controlled trials have failed to demonstrate the benefits of statins in preventing the progression of aortic stenosis [24].”
InfluentialWu, C., Pu, Q., Zou, Y., Jin, J., Lei, Y., Hu, Y., Chen, Z., & Yu, L. (2025) · Scientific Reports · doi:10.1038/s41598-025-15525-4 · Cited by 3 · see citing works
“However, these findings get challenged where subsequent study indicated the association with triglycerides was attenuated after adjustment of LDL-C 5 .”
- Authors
- Nazarzadeh, M., Pinho-Gomes, A.-C., Bidel, Z., Dehghan, A., Canoy, D., Hassaine, A., Ayala Solares, J. R., Salimi-Khorshidi, G., Smith, G. D., Otto, C. M., & Rahimi, K.
- Affiliations
- The George Institute for Global Health (GB)
- The George Institute for Global Health, University of Oxford , 1st Floor, Hayes House, 75 George Street, Oxford OX1 2BQ, UK
- Imperial College London (GB)
- University of Bristol (GB)
- University of Washington (US)
- Corresponding author
- Rahimi, Kazem
- ORCID
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-02-20
- Volume
- 41
- Issue
- 40
- Pages
- 3913-3920
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC7654932
- OpenAlex
- W3008013861
- Cited by
- 163
- References
- 53
- Citations by year
- 2026: 11 · 2025: 43 · 2024: 39 · 2023: 27 · 2022: 16 · 2021: 15 · 2020: 12
- FWCI
- 10.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Heart Journal (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by-nc)
- Bristol Research (University of Bristol) (submittedVersion, cc-by-nc)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Nazarzadeh (FS/19/36/34346)
- Pinho-Gomes (FS/19/64/34673)
- Rahimi (PG/18/65/33872)
- British Heart Foundation
- National Institute of Health Research (NIHR) Oxford Biomedical Research Centre
- Oxford Martin School
- PEAK Urban
- UKRI’s Global Challenge Research Fund (ES/P011055/1)
- George Davey Smith
- Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- aortic stenosis, plasma lipids, LDL cholesterol, HDL cholesterol, triglycerides, aortic regurgitation, mitral regurgitation, causal relationship, LDL-C lowering therapy, disease prevention
- MeSH terms
- Aortic Valve Stenosis, Humans, Lipids, Cholesterol, HDL, Cholesterol, LDL, Male, Plasma, Risk Factors, Triglycerides, Genetic Predisposition to Disease, Genome-Wide Association Study, Mendelian Randomization Analysis
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