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Risk prediction by genetic risk scores for coronary heart disease is independent of self-reported family history
Open accessAbstract
AIMS: Genetic risk scores (GRSs) have been associated with coronary heart disease (CHD) in large studies. We asked whether expanding an established 27-variant GRS (GRS27) to a 50-variant GRS (GRS50) improved CHD prediction and whether GRSs are independent of self-reported family history of CHD. METHODS AND RESULTS: The association between GRSs and incident CHD was assessed in Cox models adjusting for established risk factors in 23 595 participants of the Malmö Diet and Cancer study--a prospective, population-based study. During a median follow-up of 14.4 years, 2213 participants experienced a first CHD event. After adjustment for established risk factors, both GRS27 and GRS50 were associated with incident CHD [hazard ratio (HR) = 1.70 for high (top quintile) vs. low (bottom quintile) of GRS27; 95% confidence interval (CI): 1.48-1.94; Ptrend = 1.6 × 10(-15) and HR = 1.92 for GRS50; 95% CI: 1.67-2.20; Ptrend = 6.2 × 10(-22)]. Adding 23 single nucleotide polymorphisms (SNPs) to GRS27 improved risk prediction (P = 3 × 10(-6)). Further adjustment for self-reported family history did not appreciably change the risk estimates of either GRS27 (HR = 1.65; 95% CI: 1.45-1.89) or GRS50 (HR = 1.87; 95% CI: 1.63-2.14). The addition of GRS50 to established risk factors, including self-reported family history, improved discrimination (P < 0.0001) and reclassification (continuous net reclassification improvement index = 0.17, P < 0.0001). In young participants (below median age), those with high GRS50 had 2.4-fold greater risk (95% CI: 1.85-3.12) than those with low GRS50. CONCLUSION: The addition of 23 SNPs to an existing GRS27 improved CHD risk prediction and was independent of self-reported family history. Coronary heart disease risk assessment by GRS could be particularly useful in young individuals.
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“GPSCAD performed substantially better than two previously published polygenic scores for coronary artery disease that included 50 and 49,310 variants, respectively (Supplementary Table 7 and Supplementary Fig. 1).17,18”
From Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations (2018) · cites this paper as [17]
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“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 [23]
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“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 [23]
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Metadata
- Authors
- Tada, H., Melander, O., Louie, J. Z., Catanese, J. J., Rowland, C. M., Devlin, J. J., Kathiresan, S., & Shiffman, D.
- Affiliations
- Broad Institute (US)
- Lund University (SE)
- Quest Diagnostics (United States) (US)
- Corresponding author
- Melander, Olle
- Kathiresan, Sekar
- Shiffman, Dov
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-09-20
- Volume
- 37
- Issue
- 6
- Pages
- 561-567
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC4744619
- OpenAlex
- W1874197506
- Cited by
- 285
- References
- 23
- Citations by year
- 2026: 7 · 2025: 20 · 2024: 20 · 2023: 31 · 2022: 34 · 2021: 33 · 2020: 30 · 2019: 32 · 2018: 29 · 2017: 29 · 2016: 19 · 2015: 1
- FWCI
- 17.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- European Heart Journal (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Lund University Publications (Lund University) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Swedish Cancer Society
- Swedish Medical Research Council
- Swedish Dairy Association
- Albert Påhlsson and Gunnar Nilsson Foundations
- Malmö city council
- Japanese Circulation Society
- Massachusetts General Hospital (MGH)
- MGH
- Donovan Family Foundation
- European Research Council (StG-282255)
- Swedish Heart and Lung Foundation
- Swedish Research Council
- Novo Nordisk Foundation
- Skåne University Hospital
- Medical Faculty, Lund University;
- Albert Påhlsson Research Foundation, Region Skåne
- King Gustav V and Queen Victoria
- Foundation
- Marianne and Marcus Wallenberg Foundation
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- coronary artery disease, polygenic risk score, single nucleotide polymorphisms, family history (medicine), risk prediction, risk reclassification, net reclassification improvement, incident cardiovascular events, young adults, Malmö Diet and Cancer Study, cardiovascular risk factors, discrimination (statistics)
- MeSH terms
- Aged, Coronary Artery Disease, Epidemiologic Methods, Female, Humans, Male, Middle Aged, Pedigree, Sweden, Age Distribution, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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