Polymorphisms Associated with Cholesterol and Risk of Cardiovascular Events
Open accessAbstract
BACKGROUND: Common single-nucleotide polymorphisms (SNPs) that are associated with blood low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol modestly affect lipid levels. We tested the hypothesis that a combination of such SNPs contributes to the risk of cardiovascular disease. METHODS: We studied SNPs at nine loci in 5414 subjects from the cardiovascular cohort of the Malmö Diet and Cancer Study. We first validated the association between SNPs and either LDL or HDL cholesterol and subsequently created a genotype score on the basis of the number of unfavorable alleles. We used Cox proportional-hazards models to determine the time to the first cardiovascular event in relation to the genotype score. RESULTS: All nine SNPs showed replication of an association with levels of either LDL or HDL cholesterol. With increasing genotype scores, the level of LDL cholesterol increased from 152 mg to 171 mg per deciliter (3.9 to 4.4 mmol per liter), whereas HDL cholesterol decreased from 60 mg to 51 mg per deciliter (1.6 to 1.3 mmol per liter). During follow-up (median, 10.6 years), 238 subjects had a first cardiovascular event. The genotype score was associated with incident cardiovascular disease in models adjusted for covariates including baseline lipid levels (P<0.001). The use of the genotype score did not improve the clinical risk prediction, as assessed by the C statistic. However, there was a significant improvement in risk classification with the use of models that included the genotype score, as compared with those that did not include the genotype score. CONCLUSIONS: A genotype score of nine validated SNPs that are associated with modulation in levels of LDL or HDL cholesterol was an independent risk factor for incident cardiovascular disease. The score did not improve risk discrimination but did modestly improve clinical risk reclassification for individual subjects beyond standard clinical factors.
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A polygenic risk score has robust associations with incident coronary events.
“Our finding that a polygenic risk score has robust associations with incident coronary events is well aligned with previous studies of both primary and secondary prevention populations.16–24”
From Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease (2016) · cites this paper as [16]
When aggregated into a polygenic risk score, these risk alleles predict incident coronary events and give a continuous quantitative measure of genetic susceptibility.
“These risk alleles, when aggregated into a polygenic risk score, are predictive of incident coronary events and provide a continuous and quantitative measure of genetic susceptibility.16–24”
From Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease (2016) · cites this paper as [16]
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- Authors
- Kathiresan, S., Melander, O., Anevski, D., Guiducci, C., Burtt, N. P., Roos, C., Hirschhorn, J. N., Berglund, G., Hedblad, B., Groop, L., Altshuler, D. M., Newton-Cheh, C., & Orho-Melander, M.
- Affiliations
- Broad Institute (US)
- Lund University (SE)
- Helsinki University Hospital (FI)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2008-03-20
- Volume
- 358
- Issue
- 12
- Pages
- 1240-1249
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2394084479
- Cited by
- 696
- References
- 35
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 20 · 2023: 22 · 2022: 17 · 2021: 26 · 2020: 29 · 2019: 22 · 2018: 17 · 2017: 33 · 2016: 37 · 2015: 34 · 2014: 40 · 2013: 46 · 2012: 57
- FWCI
- 52.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Chalmers Research (Chalmers University of Technology) (submittedVersion)
- Funders
- National Institutes of Health (5k23hl083102-02)
- National Heart, Lung, and Blood Institute (K23-HL-083102, K23HL080025)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Keywords
- single nucleotide polymorphisms, LDL cholesterol, HDL cholesterol, cardiovascular risk, genotype score, cardiovascular events, risk reclassification, Malmö Diet and Cancer Study
- MeSH terms
- Cardiovascular Diseases, Coronary Disease, Female, Humans, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Myocardial Infarction, Risk Factors, ROC Curve, Multivariate Analysis, Proportional Hazards Models, Stroke, Polymorphism, Single Nucleotide
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