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Association Between a Literature-Based Genetic Risk Score and Cardiovascular Events in Women
Open accessAbstract
CONTEXT: While multiple genetic markers associated with cardiovascular disease have been identified by genome-wide association studies, their aggregate effect on risk beyond traditional factors is uncertain, particularly among women. OBJECTIVE: To test the predictive ability of a literature-based genetic risk score for cardiovascular disease. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort of 19,313 initially healthy white women in the Women's Genome Health Study followed up over a median of 12.3 years (interquartile range, 11.6-12.8 years). Genetic risk scores were constructed from the National Human Genome Research Institute's catalog of genome-wide association study results published between 2005 and June 2009. MAIN OUTCOME MEASURE: Incident myocardial infarction, stroke, arterial revascularization, and cardiovascular death. RESULTS: A total of 101 single nucleotide polymorphisms reported to be associated with cardiovascular disease or at least 1 intermediate cardiovascular disease phenotype at a published P value of less than 10(-7) were identified and risk alleles were added to create a genetic risk score. During follow-up, 777 cardiovascular disease events occurred (199 myocardial infarctions, 203 strokes, 63 cardiovascular deaths, 312 revascularizations). After adjustment for age, the genetic risk score had a hazard ratio (HR) for cardiovascular disease of 1.02 per risk allele (95% confidence interval [CI], 1.00-1.03/risk allele; P = .006). This corresponds to an absolute cardiovascular disease risk of 3% over 10 years in the lowest tertile of genetic risk (73-99 risk alleles) and 3.7% in the highest tertile (106-125 risk alleles). However, after adjustment for traditional factors, the genetic risk score did not improve discrimination or reclassification (change in c index from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [ATP III] risk score, 0; net reclassification improvement, 0.5%; [P = .24]). The genetic risk score was not associated with cardiovascular disease risk (ATP III-adjusted HR/allele, 1.00; 95% CI, 0.99-1.01). In contrast, self-reported family history remained significantly associated with cardiovascular disease in multivariable models. CONCLUSION: After adjustment for traditional cardiovascular risk factors, a genetic risk score comprising 101 single nucleotide polymorphisms was not significantly associated with the incidence of total cardiovascular disease.
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“models to combine multiple markers into a cumulative risk score are often flawed and are usually no better than traditional risk factors such as family history, demographics and non-genetic clinical phenotypes.”
From Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (2015) · cites this paper as [56]
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In the citing paper
“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 [18]
Experimental — accuracy not yet measuredIn the citing paper
“In some conditions the process of genetic counselling can be optimized and extended with cascade screening, which identifies patients at risk and enables timely treatment of affected relatives, as is the case for familial hypercholesterolaemia.72,75”
From European Guidelines on cardiovascular disease prevention in clinical practice (version 2012) (2012) · cites this paper as [72]
In the citing paper
“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 [18]
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Metadata
- Authors
- Paynter, N. P.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Paynter, Nina P.
- ORCID
- Paynter, Nina P.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2010-02-17
- Volume
- 303
- Issue
- 7
- Pages
- 631
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC2845522
- OpenAlex
- W2015060037
- Cited by
- 361
- References
- 42
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 5 · 2023: 3 · 2022: 8 · 2021: 5 · 2020: 9 · 2019: 6 · 2018: 10 · 2017: 22 · 2016: 22 · 2015: 26 · 2014: 32 · 2013: 45 · 2012: 74
- FWCI
- 37.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01hl043851-10)
- National Heart, Lung, and Blood Institute (R01HL080467, HL043851, R01‐HL043851)
- National Cancer Institute (CA 047988, R01CA047988)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Risk Factors
- Keywords
- polygenic risk score, cardiovascular disease, women, myocardial infarction, stroke, cardiovascular mortality, arterial revascularization, single nucleotide polymorphisms, family history, cardiovascular risk prediction, reclassification, risk discrimination, traditional cardiovascular risk factors, women's cardiovascular health
- MeSH terms
- Alleles, Cardiovascular Diseases, Female, Genetic Markers, Humans, Middle Aged, Phenotype, Prospective Studies, Risk, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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