Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland.
Front Immunol. 2022 Jun 21;13:909020. doi: 10.3389/fimmu.2022.909020. eCollection 2022.
The non-HLA loci conferring susceptibility to type 1 diabetes determine approximately half of the genetic disease risk, and several of them have been shown to affect immune-cell or pancreatic β-cell functions. A number of these loci have shown associations with the appearance of autoantibodies or with progression from seroconversion to clinical type 1 diabetes. In the current study, we have re-analyzed 21 of our loci with prior association evidence using an expanded DIPP follow-up cohort of 976 autoantibody positive cases and 1,910 matched controls. Survival analysis using Cox regression was applied for time periods from birth to seroconversion and from seroconversion to type 1 diabetes. The appearance of autoantibodies was also analyzed in endotypes, which are defined by the first appearing autoantibody, either IAA or GADA. Analyzing the time period from birth to seroconversion, we were able to replicate our previous association findings at , , and Novel findings included associations with , , , and . In the time period from seroconversion to clinical type 1 diabetes, prior associations with , , and were replicated, and a novel association with was observed. Analyzing the appearance of autoantibodies in endotypes, the association was specific for IAA-first. In the progression phase, was specific for IAA-first and to GADA-first. In conclusion, our results further the knowledge of the function of non-HLA risk polymorphisms in detailing endotype specificity and timing of disease development.
非 HLA 基因座与 1 型糖尿病易感性相关，大约决定了一半的遗传疾病风险，其中一些已经被证明会影响免疫细胞或胰岛 β 细胞的功能。其中一些基因座已被证明与自身抗体的出现或从血清转换到临床 1 型糖尿病的进展有关。在本研究中，我们使用先前自身抗体阳性病例的扩展 DIPP 随访队列（976 例）和 1910 例匹配对照，对具有先前关联证据的 21 个基因座进行了重新分析。使用 Cox 回归的生存分析用于从出生到血清转换以及从血清转换到 1 型糖尿病的时间段。还根据首次出现的自身抗体（IAA 或 GADA）定义的内型分析自身抗体的出现。在从出生到血清转换的时间段内，我们能够复制先前在 、 和 处的关联发现。新的发现包括与 、 、 和 的关联。在从血清转换到临床 1 型糖尿病的时间范围内，先前与 、 和 的关联得到了复制，并且观察到与 的新关联。在分析内型中自身抗体的出现时， 与 IAA 首次出现的关联是特异性的。在进展阶段， 特异性针对 IAA 首次出现， 特异性针对 IAA 至 GADA 首次出现。总之，我们的结果进一步了解了非 HLA 风险多态性的功能，详细说明了内型特异性和疾病发展的时间。
