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A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses

Ripatti, Samuli; Tikkanen, Emmi; Orho-Melander, Marju LU ; Havulinna, Aki S.; Silander, Kaisa; Sharma, Amitabh LU ; Guiducci, Candace; Perola, Markus; Jula, Antti and Sinisalo, Juha, et al. (2010) In The Lancet 376(9750). p.1393-1400
Abstract
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.... (More)
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=7.3x10(-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. (Less)
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The Lancet
volume
376
issue
9750
pages
1393 - 1400
publisher
Elsevier Limited
external identifiers
  • wos:000283627500034
  • scopus:78049314943
ISSN
1474-547X
DOI
10.1016/S0140-6736(10)61267-6
language
English
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yes
id
c1495a21-f936-47c9-be3d-8d71f5b1e5b5 (old id 1720273)
date added to LUP
2010-12-03 15:05:33
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2018-07-01 03:01:45
@article{c1495a21-f936-47c9-be3d-8d71f5b1e5b5,
  abstract     = {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=7.3x10(-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.},
  author       = {Ripatti, Samuli and Tikkanen, Emmi and Orho-Melander, Marju and Havulinna, Aki S. and Silander, Kaisa and Sharma, Amitabh and Guiducci, Candace and Perola, Markus and Jula, Antti and Sinisalo, Juha and Lokki, Marja-Liisa and Nieminen, Markku S. and Melander, Olle and Salomaa, Veikko and Peltonen, Leena and Kathiresan, Sekar},
  issn         = {1474-547X},
  language     = {eng},
  number       = {9750},
  pages        = {1393--1400},
  publisher    = {Elsevier Limited},
  series       = {The Lancet},
  title        = {A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses},
  url          = {http://dx.doi.org/10.1016/S0140-6736(10)61267-6},
  volume       = {376},
  year         = {2010},
}