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Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece.

ABSTRACT: To determine the extent to which the risk for incident coronary heart disease (CHD) increases in relation to a genetic risk score (GRS) that additively integrates the influence of high-risk alleles in nine documented single nucleotide polymorphisms (SNPs) for CHD, and to examine whether this GRS also predicts incident stroke.Genotypes at nine CHD-relevant SNPs were determined in 494 cases of incident CHD, 320 cases of incident stroke and 1345 unaffected controls drawn from the population-based Greek component of the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. An additive GRS was calculated for each study participant by adding one unit for the presence of each high-risk allele multiplied by the estimated effect size of that allele in the discovery samples. Statistical analysis was performed using logistic regression.The GRS was significantly associated with the incidence of CHD where the odds of CHD incidence in the highest quintile of the GRS were 1.74 times higher (95% confidence interval [CI]=1.25-2.43, p for trend=0.0004), compared to the lowest quintile. With respect to stroke, a weaker and non-significant positive association with GRS was apparent as the odds of stroke incidence in the highest quintile of the GRS were 1.36 times higher (95% CI=0.90-2.06, p for trend=0.188), compared to the lowest quintile.A GRS relying on nine documented "CHD-specific" SNPs is significantly predictive of CHD but it was not found to be statistically significantly associated with incident stroke.

SUBMITTER: Yiannakouris N

PROVIDER: S-EPMC3572363 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece.

Yiannakouris N N Katsoulis M M Dilis V V Parnell L D LD Trichopoulos D D Ordovas J M JM Trichopoulou A A

Atherosclerosis 20120228 1

<h4>Objective</h4>To determine the extent to which the risk for incident coronary heart disease (CHD) increases in relation to a genetic risk score (GRS) that additively integrates the influence of high-risk alleles in nine documented single nucleotide polymorphisms (SNPs) for CHD, and to examine whether this GRS also predicts incident stroke.<h4>Methods</h4>Genotypes at nine CHD-relevant SNPs were determined in 494 cases of incident CHD, 320 cases of incident stroke and 1345 unaffected controls ...[more]

PMID: 22429504

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Project description: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.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.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.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.The Wellcome Trust; Academy of Finland Center of Excellence for Complex Disease Genetics; US National Institutes of Health; the Donovan Family Foundation.

Project description:BACKGROUND:A Genetic risk score for coronary artery disease (CAD) improves the ability of predicting coronary heart disease (CHD). It is unclear whether i) the use of a CAD genetic risk score is superior to the measurement of coronary artery calcification (CAC) for CHD risk assessment and ii) the CHD risk assessment using a CAD genetic risk score differs between men and women. METHODS:We included 4041 participants (age-range: 45-76?years, 1919 men) of the Heinz Nixdorf Recall study without CHD or stroke at baseline. A standardized weighted CAD genetic risk score was constructed using 70 known genetic variants. The risk score was divided into quintiles (Q1-Q5). We specified low (Q1), intermediate (Q2-Q4) and high (Q5) genetic risk groups. Incident CHD was defined as fatal and non-fatal myocardial infarction, stroke and coronary death. The association between the genetic risk score and genetic risk groups with incident CHD was assessed using Cox models to estimate hazard ratios (HR) and 95%-confidence intervals (CI). The models were adjusted by age and sex (Model1), as well as by established CHD risk factors (RF) and CAC (Model2). The analyses were further stratified by sex and controlled for multiple testing. RESULTS:During a median follow-up time of 11.6?±?3.7?years, 343 participants experienced CHD events (219 men). Per-standard deviation (SD) increase in the genetic risk score was associated with 18% increased risk for incident CHD (Model1: p?=?0.002) which did not change after full adjustment (Model2: HR?=?1.18 per-SD (p?=?0.003)). In Model2 we observed a 60% increased CHD risk in the high (p?=?0.009) compared to the low genetic risk group. Stratifying by sex, only men showed statistically significantly higher risk for CHD (Model2: HR?=?1.23 per-SD (p?=?0.004); intermediate: HR?=?1.52 (p?=?0.04) and high: HR?=?1.88 (p?=?0.008)) with no statistically significant risk observed in women. CONCLUSION:Our results suggest that the CAD genetic risk score could be useful for CHD risk prediction, at least in men belonging to the higher genetic risk group, but it does not outbalance the value of CT-based quantification of CAC which works independently on both men and women and allows better risk stratification in both the genders.

Dataset Information

Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece.

Publications

Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece.

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