Genetic Associations with Valvular Calcification and Aortic Stenosis
Open accessAbstract
BACKGROUND: Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS: We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS: One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. CONCLUSIONS: Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).
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Several studies suggest a genetic component is involved in promoting calcific AS associated with bicuspid or tricuspid aortic valves.
“Several studies suggest that a genetic component is involved in promoting calcific AS associated with bicuspid or tricuspid aortic valves6;17;48;145.”
From Calcific aortic stenosis (2016) · cites this paper as [48]
The Discussion (page not provided) reports familial clustering of calcific valvular disease and genetic findings involving bicuspid aortic valves. The Conclusions (page not provided) associate variation at the LPA locus with aortic-valve calcification and incident clinical aortic stenosis. Our copy does not establish the claim specifically for calcific stenosis of tricuspid aortic valves. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRecent Mendelian randomization studies showed that the gene encoding apo(a), LPA, is potentially causally related to calcific aortic valve disease.
“Recent studies that used a Mendelian randomization design showed that the gene encoding apo(a) (LPA) is potentially causally related to calcific aortic valve disease48–50.”
From Calcific aortic stenosis (2016) · cites this paper as [48]
A large Mendelian randomization study identified SNP rs10455872 in the LPA gene as the only genome-wide significant SNP associated with aortic valve calcification and clinical calcific AS.
“A large study using a Mendelian randomization design identified the single nucleotide polymorphism (SNP) rs10455872 in the LPA gene as the only genome-wide significant SNP associated with the presence of aortic valve calcification and clinical calcific AS48.”
From Calcific aortic stenosis (2016) · cites this paper as [48]
Among high-risk PARTNER I Cohort A patients treated with TAVR or surgical aortic valve replacement, death from non-cardiovascular causes was more common than death from cardiovascular causes.
“Among patients treated in the high-risk Cohort A of the PARTNER I trial with TAVR or surgical AVR (Table 4), death from non-cardiovascular causes was more common than death from cardiovascular causes48.”
From Calcific aortic stenosis (2016) · cites this paper as [48]
The Methods (page unavailable) describe population-based genetic and CT studies, while the Results section on incident aortic stenosis (page unavailable) reports valve-replacement outcomes in the MDCS, not the PARTNER I trial. Searches for PARTNER I Cohort A and for cardiovascular versus non-cardiovascular deaths found no passage comparing causes of death after TAVR or surgical replacement. (LLM, conf=0.78)
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- Authors
- 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., Malhotra, R., O'Brien, K. D., Kamstrup, P. R., Nordestgaard, B. G., Tybjaerg-Hansen, A., Allison, M. A., Aspelund, T., Criqui, M. H., Heckbert, S. R., Hwang, S.-J., Liu, Y., Sjogren, M., van der Pals, J., Kälsch, H., Mühleisen, T. W., Nöthen, M. M., Cupples, L. A., Caslake, M., Di Angelantonio, E., Danesh, J., Rotter, J. I., Sigurdsson, S., Wong, Q., Erbel, R., Kathiresan, S., Melander, O., Gudnason, V., O'Donnell, C. J., & Post, W. S.
- Affiliations
- National Institutes of Health (US)
- Johns Hopkins University (US)
- University of Washington (US)
- Broad Institute (US)
- University of Iceland (IS)
- University of Duisburg-Essen (DE)
- University of California, Los Angeles (US)
- Harvard University (US)
- University of Copenhagen (DK)
- University of California San Diego (US)
- Wake Forest University (US)
- University of Bonn (DE)
- Boston University (US)
- University of Glasgow (GB)
- University of Cambridge (GB)
- Cedars-Sinai Medical Center (US)
- Icelandic Heart Association (IS)
- Lund University (SE)
- ORCID
- Thanassoulis, George
- Owens, David S.
- Smith, Albert V.
- Peloso, Gina M.
- Kerr, Kathleen F.
- Pechlivanis, Sonali
- Budoff, Matthew J.
- Harris, Tamara B.
- Malhotra, Rajeev
- Kamstrup, Pia R.
- Nordestgaard, Børge G.
- Allison, Matthew A.
- Aspelund, Thor
- Criqui, Michael H.
- Heckbert, Susan R.
- Hwang, Shih-Jen
- Nöthen, Markus M.
- Cupples, L. Adrienne
- Danesh, John
- Rotter, Jerome I.
- Sigurdsson, Sigurdur
- Wong, Quenna
- Kathiresan, Sekar
- Melander, Olle
- Gudnason, Vilmundur
- Post, Wendy S.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2013-02-07
- Volume
- 368
- Issue
- 6
- Pages
- 503-512
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3766627
- OpenAlex
- W2107134698
- Cited by
- 1,008
- References
- 48
- Citations by year
- 2026: 76 · 2025: 83 · 2024: 73 · 2023: 72 · 2022: 84 · 2021: 83 · 2020: 103 · 2019: 89 · 2018: 64 · 2017: 79 · 2016: 67 · 2015: 47 · 2014: 57 · 2013: 30
- FWCI
- 45.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- DZNE Pub (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0512-10165)
- British Heart Foundation (RG/08/014/24067)
- Novo Nordisk Fonden (NNF13OC0005339)
- National Institutes of Health (n01hc95164-17-0-1, n01ag12100-57-0-2, n01hc95165-34-0-1, n01hc95161-24-0-1, n01hc095169-003, UL1TR000124, n01hc65226-6-0-0, n01hc95166-21-0-1, n01hc95162-31-0-1, n01hc95168-27-0-1, n01hc95160-18-0-1, n01hc095167-000, n01hc25195-41-0-1, n01hc95163-22-0-1, n02hl64278-6-0-0, n01hc95159-40-0-1, KL2TR002317)
- Medical Research Council (MR/L003120/1)
- National Institute on Aging (N01-AG012100)
- National Heart, Lung, and Blood Institute (R01HL071205, N01-HC-65226, N01 HC-95159, N01-HC-95160, N01-HC095169, R01HL071739, N01 HC-95168, N01-HC-095165, R01HL071252, N01 HC95167, (N01-HC-95163, N01 HC095163, N01‐HC25195, R01HL071259, N01 HC-95161, N01 HC95165, N01HC95164, R01HL071251, N02 HL064278, N01-HC-095159, N01 HC095168, N02- HL-64278, N01-HC-095162, N01-HC-095161, R01HL071051, R01HL071250, N01-HC-025195, N01 HC065226, R01HL105756, N01-HC-095160, N01 HC095166, N01 HC095164, N01‐HC‐95166, R01HL071258, N01 HC-95162, N01 HC95169)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)
- National Center for Research Resources (UL1RR024156, UL1RR025005, RR024156)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- valve calcification, aortic stenosis, mitral annular calcification, lipoprotein(a), LPA gene, genetic susceptibility, aortic valve replacement
- MeSH terms
- Aged, Aortic Valve, Aortic Valve Stenosis, Calcinosis, Female, Heart Valve Diseases, Humans, Male, Middle Aged, Mitral Valve, Tomography, X-Ray Computed, Linear Models, Lipoprotein(a), Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis
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