Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes.
Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes.
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DOI：
10.2337/db15-1690
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发表时间：
2016-07
期刊：
影响因子：
7.7
通讯作者：
Hattersley AT
中科院分区：
文献类型：
--
作者：
Patel KA;Oram RA;Flanagan SE;De Franco E;Colclough K;Shepherd M;Ellard S;Weedon MN;Hattersley AT
区分单基因糖尿病患者和1型糖尿病(T1D)患者对于正确诊断、治疗和选择患者进行基因发现研究非常重要。我们评估了由与T1D相关的常见基因变异产生的T1D遗传风险评分(T1D-GRS)是否提供了一种区分单基因糖尿病和T1D的新方法。T1D-GRS对已证实的MODY(n=805)和T1D(n=1963)具有高度的区分性(ROC-AUC=0.87)。T1D-GRS为>；0.280(>；50百分位数)表示T1D(特异度94%，敏感度50%)。然后，我们分析了242名接受过所有已知新生儿糖尿病基因检测的欧洲白人新生儿糖尿病(NDM)患者的T1D-GRS。在GRS<；第5个T1D百分位数、50-75个T1D百分位数和>；75个T1D百分位数的患者中，单基因NDM的确诊率分别为90%、59%和8%。将GRS第50个T1D百分位数截断值应用于48名没有已知遗传原因的NDM患者，通过突出可能的早发性T1D患者(GRS>；50个T1D百分位数)来识别那些最有可能具有新的单基因病因学的患者，这些患者被诊断得较晚，症状表现较少，但与已证实的单基因NDM相比，具有额外的自身免疫特征。T1D-GRS是一种新的工具，可以提高生物标记物在区分单基因糖尿病和T1D糖尿病中的应用。
Distinguishing patients with monogenic diabetes from Type 1 diabetes (T1D) is important for correct diagnosis, treatment and to select patients for gene discovery studies. We assessed whether a T1D genetic risk score (T1D-GRS) generated from T1D-associated common genetic variants provides a novel way to discriminate monogenic diabetes from T1D. The T1D-GRS was highly discriminative of proven MODY (n=805) and T1D (n=1963) (ROC-AUC=0.87). A T1D-GRS of >0.280 (>50th T1D centile) was indicative of T1D (94% specificity, 50% sensitivity). We then analyzed the T1D-GRS in 242 White-European patients with neonatal diabetes (NDM) who had been tested for all known neonatal diabetes genes. Monogenic NDM was confirmed in 90%, 59% and 8% in patients with GRS <5th T1D centile, 50-75th T1D centile and >75th T1D centile, respectively. Applying a GRS 50th T1D centile cut-off in 48 NDM patients with no known genetic cause, identified those most likely to have a novel monogenic etiology by highlighting patients with probable early-onset T1D (GRS >50th T1D centile) who were diagnosed later, had less syndromic presentation but had additional autoimmune features compared to proven monogenic NDM. The T1D-GRS is a novel tool to improve the use of biomarkers in the discrimination of monogenic diabetes from T1D.