A strategy to find gene combinations that identify children who progress rapidly to type 1 diabetes after islet autoantibody seroconversion
A strategy to find gene combinations that identify children who progress rapidly to type 1 diabetes after islet autoantibody seroconversion
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DOI：
10.1007/s00592-013-0526-2
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发表时间：
2014-06-01
影响因子：
3.8
通讯作者：
Ziegler, Anette-Gabriele
中科院分区：
文献类型：
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作者：
Bonifacio, Ezio;Krumsiek, Jan;Ziegler, Anette-Gabriele
我们最近开发了一种新的方法，能够识别基因组合，以获得最大的疾病风险分层。1型糖尿病具有临床前阶段，包括血清转化为自身免疫和随后进展为糖尿病。在这里，我们应用我们的基因组合的方法来确定组合，有助于胰岛自身免疫或从胰岛自身抗体糖尿病发作的进展。我们检测了12个1型糖尿病易感基因（INS、ERBB 3、PTPN 2、IFIH 1、PTPN 22、KIAA 0350、CD 25、CTLA 4、SH 2B 3、IL 2、IL 18 RAP、IL 10），这些基因来自于父母患有1型糖尿病的儿童队列，并从出生起进行前瞻性随访。最具预测性的组合随后应用于较小的验证队列。这些基因的组合对胰岛自身免疫的风险只有轻微的影响，但可以显著改变胰岛自身抗体阳性儿童发展为糖尿病的风险。INS、IFIH 1、IL 18 RAP、CD 25和IL 2五个基因的风险等位基因评分提供了最大的区分力，可以识别80%的胰岛自身抗体阳性儿童在血清转换6年内进展为糖尿病，并区分高风险（6年内63%; 95%CI 45- 81%）和低风险（6年内11%; 95%CI 0.1- 22%; p = 4 x 10（-5））抗体阳性儿童。这五个基因的危险分层在第二组胰岛自身抗体儿童中得到证实。这些发现突出了一旦自身免疫启动可能影响β细胞破坏过程速率的基因，并可能有助于识别快速进展为糖尿病的胰岛自身抗体阳性受试者。
We recently developed a novel approach capable of identifying gene combinations to obtain maximal disease risk stratification. Type 1 diabetes has a preclinical phase including seroconversion to autoimmunity and subsequent progression to diabetes. Here, we applied our gene combination approach to identify combinations that contribute either to islet autoimmunity or to the progression from islet autoantibodies to diabetes onset. We examined 12 type 1 diabetes susceptibility genes (INS, ERBB3, PTPN2, IFIH1, PTPN22, KIAA0350, CD25, CTLA4, SH2B3, IL2, IL18RAP, IL10) in a cohort of children of parents with type 1 diabetes and prospectively followed from birth. The most predictive combination was subsequently applied to a smaller validation cohort. The combinations of genes only marginally contributed to the risk of developing islet autoimmunity, but could substantially modify risk of progression to diabetes in islet autoantibody-positive children. The greatest discrimination was provided by risk allele scores of five genes, INS, IFIH1, IL18RAP, CD25, and IL2 genes, which could identify 80 % of islet autoantibody-positive children who progressed to diabetes within 6 years of seroconversion and discriminate high risk (63 % within 6 years; 95 % CI 45-81 %) and low risk (11 % within 6 years; 95 % CI 0.1-22 %; p = 4 x 10(-5)) antibody-positive children. Risk stratification by these five genes was confirmed in a second cohort of islet autoantibody children. These findings highlight genes that may affect the rate of the beta-cell destruction process once autoimmunity has initiated and may help to identify islet autoantibody-positive subjects with rapid progression to diabetes.