A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses.
A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses.
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DOI：
10.1016/s0140-6736(10)61267-6
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发表时间：
2010-10-23
期刊：
影响因子：
168.9
通讯作者：
Kathiresan, Sekar
中科院分区：
文献类型：
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作者：
Ripatti, Samuli;Tikkanen, Emmi;Orho-Melander, Marju;Havulinna, Aki S.;Silander, Kaisa;Sharma, Amitabh;Guiducci, Candace;Perola, Markus;Jula, Antti;Sinisalo, Juha;Lokki, Marja-Liisa;Nieminen, Markku S.;Melander, Olle;Salomaa, Veikko;Peltonen, Leena;Kathiresan, Sekar
在全基因组关联研究中，对冠心病患者和对照组的比较揭示了几种与冠心病相关的单核苷酸多态性（SNP）。我们的目的是建立这些发现的外部效度，并使用前瞻性队列设计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与冠心病的相关性，包括与发现样本不同的参与者（3829名患有冠心病的参与者和48897名无冠心病的对照者）和前瞻性队列设计，包括来自芬兰和瑞典的30725名无心血管疾病的参与者。 我们将13个SNPs作为多位点遗传风险评分模型，并使用考克斯比例风险模型来估计遗传风险评分与冠心病事件的相关性。对于病例对照分析，我们使用逻辑回归分析了单个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，1264名参与者在中位数为10.7年的随访期间（IQR 6.7 - 13.6）首次发生冠心病事件。遗传风险评分与首次冠心病事件相关。与遗传风险得分最低的五分之一相比，在调整传统风险因素的模型中，最高五分之一的参与者患冠心病的风险增加了1.66倍（95% CI 1.35 - 2.04，线性趋势的p值= 7.3 ×10−10）。家族史的调整并没有改变这些估计。与传统危险因素和家族史相比，遗传风险评分并没有改善C指数（p= 0.19），也没有对净重新分类改善产生显著影响（2.2%，p= 0.18）;但是，它对综合区分指数有很小的影响（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20%的欧洲血统个体首次冠心病事件的风险增加约70%。这组SNP的潜在临床用途仍有待确定。Wellcome Trust;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。
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.