Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis
Open accessAbstract
Background Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS.Methods We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls.Results In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24-1.52, p = 6.9 × 10-10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31-1.79) compared to those with CAD (OR 1.27; 95%CI 1.12-1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88-0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27-1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95-1.02).Conclusions Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS.
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- Authors
- Trenkwalder, T., Nelson, C. P., Musameh, M. D., Mordi, I. R., Kessler, T., Pellegrini, C., Debiec, R., Rheude, T., Lazovic, V., Zeng, L., Martinsson, A., Gustav Smith, J., Gådin, J. R., Franco-Cereceda, A., Eriksson, P., Nielsen, J. B., Graham, S. E., Willer, C. J., Hveem, K., Kastrati, A., Braund, P. S., Palmer, C. N. A., Aracil, A., Husser, O., Koenig, W., Schunkert, H., Lang, C. C., Hengstenberg, C., & Samani, N. J.
- Affiliations
- Deutsches Herzzentrum München (DE)
- University of Leicester (GB)
- University of Dundee (GB)
- Sahlgrenska University Hospital (SE)
- Karolinska University Hospital (SE)
- University of Michigan (US)
- Norwegian University of Science and Technology (NO)
- German Centre for Cardiovascular Research (DE)
- Corresponding author
- Lang, Chim C.
- Hengstenberg, Christian
- Samani, Nilesh J.
- ORCID
- Trenkwalder, Teresa
- Nelson, Christopher P.
- Mordi, Ify R.
- Kessler, Thorsten
- Pellegrini, Costanza
- Rheude, Tobias
- Zeng, Lingyao
- Martinsson, Andreas
- Gådin, Jesper R.
- Eriksson, Per
- Nielsen, Jonas B.
- Graham, Sarah E.
- Willer, Cristen J.
- Hveem, Kristian
- Kastrati, Adnan
- Braund, Peter S.
- Aracil, Amparo
- Schunkert, Heribert
- Lang, Chim C.
- Hengstenberg, Christian
- Samani, Nilesh J.
- Venue
- International Journal of Cardiology
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 276
- Pages
- 212-217
- ISSN
- 0167-5273 (ISSN-L)
- PMC
- PMC6878659
- OpenAlex
- W2901433620
- Cited by
- 18
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 4
- FWCI
- 0.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by-nc-nd)
- Figshare (submittedVersion, cc-by-nc-nd)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by-nc-nd)
- Lund University Publications (Lund University) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- British Heart Foundation (PG/16/32/32132, PG/14/4/30539)
- NHS Education for Scotland
- Chief Scientist Office (PCL17/07)
- European Research Council
- Swedish Heart-Lung Foundation
- Lund University
- Swedish Research Council
- Crafoord Foundation
- Skåne University Hospital
- Corona Foundation (S199/10070/2017)
- 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 › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- aortic stenosis, coronary artery disease, LPA gene, 9p21 locus, genetic risk variants, rs10455872, rs1333049, calcific aortic stenosis, genetic association, disease co-occurrence
- MeSH terms
- Aged, Aortic Valve Stenosis, Chromosomes, Human, Pair 9, Coronary Artery Disease, Female, Humans, Male, Middle Aged, Genetic Variation, Case-Control Studies, Lipoprotein(a), Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci
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