Elevated Lipoprotein(a) and Risk of Aortic Valve Stenosis in the General Population
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Objectives The purpose of this study was to determine whether elevated lipoprotein(a) levels and corresponding LPA risk genotypes (rs10455872, rs3798220, kringle IV type 2 repeat polymorphism) prospectively associate with increased risk of aortic valve stenosis (AVS).Background The etiologic basis of AVS is unclear. Recent data implicate an LPA genetic variant (rs10455872), associated with Lp(a) levels, in calcific AVS.Methods We combined data from 2 prospective general population studies, the Copenhagen City Heart Study (1991 to 2011; n = 10,803) and the Copenhagen General Population Study (2003 to 2011; n = 66,877), following up 77,680 Danish participants for as long as 20 years, during which time 454 were diagnosed with AVS. We conducted observational and genetic instrumental variable analyses in a Mendelian randomization study design.Results Elevated Lp(a) levels were associated with multivariable adjusted hazard ratios for AVS of 1.2 (95% confidence interval [CI]: 0.8 to 1.7) for 22nd to 66th percentile levels (5 to 19 mg/dl), 1.6 (95% CI: 1.1 to 2.4) for 67th to 89th percentile levels (20 to 64 mg/dl), 2.0 (95% CI: 1.2 to 3.4) for 90th to 95th percentile levels (65 to 90 mg/dl), and 2.9 (95% CI: 1.8 to 4.9) for levels greater than 95th percentile (>90 mg/dl), versus levels less than the 22nd percentile (<5 mg/dl; trend, p < 0.001). Lp(a) levels were elevated among carriers of rs10455872 and rs3798220 minor alleles, and of low number of KIV-2 repeats (trend, all p < 0.001). Combining all genotypes, instrumental variable analysis yielded a genetic relative risk for AVS of 1.6 (95% CI: 1.2 to 2.1) for a 10-fold Lp(a) increase, comparable to the observational hazard ratio of 1.4 (95% CI: 1.2 to 1.7) for a 10-fold increase in Lp(a) plasma levels.Conclusions Elevated Lp(a) levels and corresponding genotypes were associated with increased risk of AVS in the general population, with levels >90 mg/dl predicting a threefold increased risk.
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Recent 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 [49]
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- Authors
- Kamstrup, P. R., Tybjærg-Hansen, A., & Nordestgaard, B. G.
- Affiliations
- Herlev Hospital (DK)
- University of Copenhagen (DK)
- Corresponding author
- Nordestgaard, Børge G.
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 63
- Issue
- 5
- Pages
- 470-477
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2086153196
- Cited by
- 595
- References
- 30
- Citations by year
- 2026: 40 · 2025: 66 · 2024: 54 · 2023: 50 · 2022: 63 · 2021: 40 · 2020: 50 · 2019: 64 · 2018: 33 · 2017: 45 · 2016: 43 · 2015: 29 · 2014: 15 · 2013: 2
- FWCI
- 20.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Danish Heart Foundation
- Danish Council for Independent Research Medical Sciences
- IMK Almene Fund
- Johan and Lise Boserup's Fund
- 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
- lipoprotein(a), aortic stenosis, rs10455872, rs3798220, genetic risk, calcific aortic valve disease, Mendelian randomization, cardiovascular risk factors, Copenhagen City Heart Study, Copenhagen General Population Study, general population cohort
- MeSH terms
- Aged, Aortic Valve Stenosis, Denmark, Female, Humans, Hyperlipoproteinemias, Male, Middle Aged, Population Surveillance, Prospective Studies, Risk Factors, Severity of Illness Index, Biomarkers, Incidence, Prevalence, Lipoprotein(a), Risk Assessment
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