Immunogenetics Laboratory, University of Turku, Turku, Finland; Department of Pediatrics, Turku University Hospital, University of Turku, Turku, Finland.
Pediatr Diabetes. 2013 Nov;14(7):490-6. doi: 10.1111/pedi.12046. Epub 2013 May 31.
More than 50 loci outside the human leukocyte antigen (HLA) region have been confirmed to affect type 1 diabetes (T1D) risk but their effect on β-cell autoimmunity is poorly defined. We analyzed the association of 35 single nucleotide polymorphism (SNP) markers previously associated with T1D with the presence of disease-predictive autoantibodies at the time of T1D diagnosis.
The study cohort comprised 1554 children diagnosed with T1D before the age of 15 yr. The associations between various genotypes and positivity for antibodies against islet cells [islet cell antibodies (ICA)], insulin [insulin autoantibodies (IAA)], glutamic acid decarboxylase (GADA), islet antigen 2 (IA2A), and zinc transporter 8 (ZnT8A) were analyzed.
INS gene polymorphism rs689 and IKZF4 polymorphism (rs1701704) were strongly associated with IAA positivity at the time of T1D diagnosis (p = 0.000004 and 0.00044, respectively). The presence of the T1D-risk conferring INS AA genotype was associated with IAA. In contrast, the presence of the susceptible C allele of the IKZF4 marker was inversely associated with IAA. The INS and IKZF4 polymorphisms were not significantly associated with ICA, GADA, IA2A, or ZnT8A positivity.
Both INS and IKZF4 polymorphisms modified the probability of IAA positivity at time of T1D onset but the inverse association of IKZF4 risk allele with IAA suggests that the IKZF4 polymorphism is involved in a pathway of β-cell autoimmunity alternate to the route characterized by IAA and development of T1D in early childhood. The IKZF4 gene encodes Eos, which is implicated to play an important role in Treg programming where this gene might exert its influence on T1D risk.
除人类白细胞抗原（HLA）区域外，已有 50 多个位点被证实可影响 1 型糖尿病（T1D）风险，但它们对β细胞自身免疫的影响尚不清楚。我们分析了先前与 T1D 相关的 35 个单核苷酸多态性（SNP）标记物与 T1D 诊断时疾病预测性自身抗体存在的关联。
该研究队列包括 1554 名在 15 岁之前被诊断为 T1D 的儿童。分析了各种基因型与胰岛细胞自身抗体（ICA）、胰岛素自身抗体（IAA）、谷氨酸脱羧酶（GADA）、胰岛抗原 2（IA2A）和锌转运体 8（ZnT8A）阳性之间的关联。
INS 基因多态性 rs689 和 IKZF4 多态性（rs1701704）与 T1D 诊断时 IAA 阳性密切相关（p 值分别为 0.000004 和 0.00044）。T1D 风险赋予的 INS AA 基因型的存在与 IAA 相关。相比之下，IKZF4 标记物易感 C 等位基因的存在与 IAA 呈负相关。INS 和 IKZF4 多态性与 ICA、GADA、IA2A 或 ZnT8A 阳性无显著相关性。
INS 和 IKZF4 多态性均改变了 T1D 发病时 IAA 阳性的概率，但 IKZF4 风险等位基因与 IAA 的负相关表明，IKZF4 多态性参与了不同于 IAA 和幼年儿童 T1D 发展的途径的β细胞自身免疫途径。IKZF4 基因编码 Eos，该基因被认为在 Treg 编程中发挥重要作用，该基因可能对 T1D 风险产生影响。
