1 型糖尿病遗传风险评分可预测高危个体胰岛自身免疫的进展和 1 型糖尿病的发生。
A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk.
出版信息
Diabetes Care. 2018 Sep;41(9):1887-1894. doi: 10.2337/dc18-0087. Epub 2018 Jul 12.
OBJECTIVE
We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.
RESEARCH DESIGN AND METHODS
We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.
RESULTS
Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; = 0.0002).
CONCLUSIONS
The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
目的
我们检测了 1 型糖尿病（T1D）遗传风险评分（GRS）预测高危个体胰岛自身免疫和 T1D 进展的能力。
研究设计和方法
我们研究了参加 1,244 项 TrialNet 预防研究的参与者（1 型糖尿病患者的无糖尿病亲属，且有一种或多种自身抗体阳性），这些参与者使用 Illumina ImmunoChip 进行了基因分型（初次自身抗体测定时的中位年龄[范围]为 11.1 岁[1.2-51.8]，48%为男性，80.5%为非西班牙裔白人，中位随访时间为 5.4 年）。在 291 名筛查时存在单一阳性自身抗体的参与者中，有 157 名进展为多种自身抗体阳性，55 名发展为糖尿病。在 953 名筛查时存在多种阳性自身抗体的参与者中，有 419 名发展为糖尿病。我们从 30 个与 T1D 相关的单核苷酸多态性中计算了 T1D GRS。我们使用多变量 Cox 回归模型、时间依赖性接受者操作特征曲线和曲线下面积（AUC）测量来评估 T1D GRS、年龄、性别、糖尿病预防试验 1 型（DPT-1）风险评分、阳性自身抗体数量或类型、HLA DR3/DR4-DQ8 状态和种族/民族的预后效用。我们使用递归分区分析来确定连续变量的截断点。
结果
调整 DPT-1 风险评分、年龄、阳性自身抗体数量、性别和种族后，更高的 T1D GRS 显著增加了进展为 T1D 的速度（每增加 0.05 的 HR 为 1.29，95%CI 为 1.06-1.6； = 0.011）。进展为 T1D 最好通过包含 GRS、阳性自身抗体数量、DPT-1 风险评分和年龄的综合模型来预测（7 年时间综合 AUC=0.79，5 年 AUC=0.73）。在调整年龄、自身抗体类型、种族和性别后，更高的 GRS 与从单一到多种阳性自身抗体的进展速度增加显著相关（GRS>0.295 的 HR 为 2.27，95%CI 为 1.47-3.51； = 0.0002）。
结论
T1D GRS 可独立预测 T1D 的进展，并在自身抗体阳性亲属的 T1D 各阶段改善预测。
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