A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses
Open accessAbstract
Background Comparison of patients with coronary heart disease and controls in genome-wide association studies has revealed several single nucleotide polymorphisms (SNPs) associated with coronary heart disease. We aimed to establish the external validity of these findings and to obtain more precise risk estimates using a prospective cohort design.Methods We tested 13 recently discovered SNPs for association with coronary heart disease in a case-control design including participants differing from those in the discovery samples (3829 participants with prevalent coronary heart disease and 48,897 controls free of the disease) and a prospective cohort design including 30,725 participants free of cardiovascular disease from Finland and Sweden. We modelled the 13 SNPs as a multilocus genetic risk score and used Cox proportional hazards models to estimate the association of genetic risk score with incident coronary heart disease. For case-control analyses we analysed associations between individual SNPs and quintiles of genetic risk score using logistic regression.Findings In prospective cohort analyses, 1264 participants had a first coronary heart disease event during a median 10·7 years' follow-up (IQR 6·7-13·6). Genetic risk score was associated with a first coronary heart disease event. When compared with the bottom quintile of genetic risk score, participants in the top quintile were at 1·66-times increased risk of coronary heart disease in a model adjusting for traditional risk factors (95% CI 1·35-2·04, p value for linear trend=7·3×10(-10)). Adjustment for family history did not change these estimates. Genetic risk score did not improve C index over traditional risk factors and family history (p=0·19), nor did it have a significant effect on net reclassification improvement (2·2%, p=0·18); however, it did have a small effect on integrated discrimination index (0·004, p=0·0006). Results of the case-control analyses were similar to those of the prospective cohort analyses.Interpretation Using a genetic risk score based on 13 SNPs associated with coronary heart disease, we can identify the 20% of individuals of European ancestry who are at roughly 70% increased risk of a first coronary heart disease event. The potential clinical use of this panel of SNPs remains to be defined.Funding The Wellcome Trust; Academy of Finland Center of Excellence for Complex Disease Genetics; US National Institutes of Health; the Donovan Family Foundation.
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Large-scale GWAS have accounted for less than one-fifth of the cardiovascular risk attributable to genetic determinants.
“Despite extensive investigations in search of causal genetic variants, such as large-scale GWAS, less than one-fifth of attributable cardiovascular risk has been accounted for from genetic determinants (3,4).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [4]
Previous GPS studies had limited success, providing insufficient risk stratification for clinical utility, for example identifying 20% of a population at 1.4-fold increased risk.
“Previous studies to create GPS had only limited success, providing insufficient risk stratification for clinical utility (for example, identifying 20% of a population at 1.4-fold increased risk relative to the rest of the population).12”
From Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations (2018) · cites this paper as [12]
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 [17]
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 [17]
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- Authors
- Ripatti, S., Tikkanen, E., Orho-Melander, M., Havulinna, A. S., Silander, K., Sharma, A., Guiducci, C., Perola, M., Jula, A., Sinisalo, J., Lokki, M.-L., Nieminen, M. S., Melander, O., Salomaa, V., Peltonen, L., & Kathiresan, S.
- Affiliations
- University of Helsinki (FI)
- Finnish Institute for Health and Welfare (FI)
- Lund University (SE)
- Broad Institute (US)
- Helsinki University Hospital (FI)
- Corresponding author
- Ripatti, Samuli
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 376
- Issue
- 9750
- Pages
- 1393-1400
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC2965351
- OpenAlex
- W2137249087
- Cited by
- 562
- References
- 33
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 15 · 2023: 31 · 2022: 29 · 2021: 25 · 2020: 43 · 2019: 42 · 2018: 42 · 2017: 37 · 2016: 47 · 2015: 38 · 2014: 38 · 2013: 37 · 2012: 71
- FWCI
- 27.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- the Wellcome Trust (WT089062/Z/09/Z, WT089061/Z/09/Z, R01 HL087676)
- US National Institutes of Health
- the Center of Excellence for Complex Disease Genetics of the Academy of Finland (213506, 129680)
- the Academy of Finland (129494)
- Finnish Foundation for Cardiovascular Research and Finnish Academy Salve Program (129322)
- 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
- coronary artery disease, single nucleotide polymorphisms, genetic risk prediction, external validation, incident coronary heart disease, risk reclassification, family history, European ancestry, cardiovascular risk factors
- MeSH terms
- Adult, Coronary Disease, Female, Genotype, Humans, Male, Middle Aged, Myocardial Infarction, Proportional Hazards Models, Case-Control Studies, Risk Assessment, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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