Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score.
Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score.
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DOI：
10.1016/s1474-4422(09)70275-3
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发表时间：
2009-12
期刊：
影响因子：
48
通讯作者：
Karlson, Elizabeth W.
中科院分区：
文献类型：
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作者：
De Jager, Philip L.;Chibnik, Lori B.;Cui, Jing;Reischl, Joachim;Lehr, Stephan;Simon, K. Claire;Aubin, Cristin;Bauer, David;Heubach, Juergen F.;Sandbrink, Rupert;Tyblova, Michaela;Lelkova, Petra;Havrdova, Eva;Pohl, Christoph;Horakova, Dana;Ascherio, Alberto;Hafler, David A.;Karlson, Elizabeth W.
预测多发性硬化症的易感性可能具有重要的临床应用，无论是作为诊断算法的一部分，还是作为前瞻性研究中识别高危个体的工具。在这里，我们研究了基于遗传易感基因座的多发性硬化症（MS）风险综合指标的实用性。其次，我们评估了与MS易感性相关的环境风险因素的附加效应。我们创建了一个加权遗传风险评分（wGRS），其中包括16个MS易感性位点。我们使用来自（1）2215例MS病例和2189例对照的数据测试了我们的模型（衍生样品），（2）从几个MS治疗试验中获得的1340例病例和1109例对照的验证集（TT样品），和（3）来自美国护士健康研究I和II（NHS）的143例病例和281例对照的第二验证集我们也有关于他们暴露于吸烟和EB病毒（EBV）的信息。.在所有数据集中，wGRS与平均值的标准差> 1.25的患者具有显著更高的MS比值比。纯遗传模型的曲线下面积为0.70，性别+遗传模型的曲线下面积在衍生样本中为0.74（P <0.0001），在TT队列中为0.64和0.72（P <0.0001）。类似地，考虑吸烟和对EBV的免疫应答将遗传模型的AUC 0.64提高到NHS队列中的0.68（P =0.02）。wGRS似乎与临床孤立综合征向MS的转化无关。目前将16个易感等位基因组合为wGRS适度预测MS风险，并在独立受试者样本中显示一致的区分能力，并通过考虑非遗传风险因素得到增强。
Predicting susceptibility to multiple sclerosis may have important clinical applications either as part of a diagnostic algorithm or as a tool with which to identify high-risk individuals for prospective studies. Here, we examine the utility of an aggregate measure of risk of multiple sclerosis (MS) based on genetic susceptibility loci. Secondarily, we assess the added effect of environmental risk factors that have been associated with susceptibility for MS. We created a weighted genetic risk score (wGRS) that includes 16 MS susceptibility loci. We tested our model using data from (1) 2215 MS cases and 2189 controls (derivation samples), (2) a validation set of 1340 cases and 1109 controls taken from several MS therapeutic trials (TT samples), and (3) a second validation set of 143 cases and 281 controls from the U.S. Nurses’ Health Studies I and II (NHS) for whom we also have information regarding exposure to smoking and Epstein-Barr Virus (EBV). . Patients with wGRS > 1.25 standard deviations from the mean had a significantly higher odds ratio for MS in all datasets. The area under the curve for a purely genetic model was 0.70 and for a gender + genetic model was 0.74 in the derivation samples (P <0.0001), 0.64 and 0.72 in the TT cohort (P <0.0001). Similarly, consideration of smoking and immune response to EBV enhanced the AUC of 0.64 for the genetic model to 0.68 in the NHS cohort (P =0.02). The wGRS does not appear to be correlated with conversion of a clinically isolated syndrome to MS. The current combination of 16 susceptibility alleles into a wGRS modestly predicts MS risk and shows consistent discriminatory ability in independent subject samples and is enhanced by considering non-genetic risk factors.