Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. samuli.ripatti@fi mm.fi
Lancet. 2010 Oct 23;376(9750):1393-400. doi: 10.1016/S0140-6736(10)61267-6.
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.
全基因组关联研究比较了冠心病患者和对照者，发现了几个与冠心病相关的单核苷酸多态性（SNP）。我们旨在通过前瞻性队列设计建立这些发现的外部有效性，并获得更精确的风险估计。
我们在病例对照设计中测试了 13 个最近发现的 SNP 与冠心病的关联，该设计包括与发现样本不同的参与者（3829 名患有冠心病的患者和 48897 名无该病的对照者），以及一项包括芬兰和瑞典 30725 名无心血管疾病的前瞻性队列设计。我们将 13 个 SNP 建模为多基因遗传风险评分，并使用 Cox 比例风险模型估计遗传风险评分与新发冠心病的关联。对于病例对照分析，我们使用逻辑回归分析了个体 SNP 与遗传风险评分五分位数之间的关联。
在前瞻性队列分析中，中位 10.7 年的随访期间（IQR 6.7-13.6）有 1264 名参与者发生了首次冠心病事件。遗传风险评分与首次冠心病事件相关。与遗传风险评分最低五分位数的参与者相比，最高五分位数的参与者在调整传统危险因素后发生冠心病的风险增加 1.66 倍（95%CI 1.35-2.04，线性趋势检验 p 值=7.3×10(-10)）。调整家族史并不能改变这些估计值。遗传风险评分并没有改善传统危险因素和家族史的 C 指数（p=0.19），也没有对净重新分类改善有显著影响（2.2%，p=0.18）；然而，它对综合鉴别指数有较小的影响（0.004，p=0.0006）。病例对照分析的结果与前瞻性队列分析的结果相似。
使用基于与冠心病相关的 13 个 SNP 的遗传风险评分，我们可以确定约 20%的欧洲血统个体首次冠心病事件的风险增加了约 70%。该 SNP 面板的潜在临床应用仍有待确定。
英国惠康信托基金会；芬兰科学院复杂疾病遗传学卓越中心；美国国立卫生研究院；多诺万家庭基金会。
