Dysfunction of FOXP3-positive regulatory T cells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D-associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non-HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody-positive at-risk subjects, and 215 islet autoantibody-negative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 × 10-6 ) and naïve (p = 4 × 10-5 ) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody-negative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for naïve Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood.

中文翻译：

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与1型糖尿病相关的PTPN22基因多态性与循环调节性T细胞的频率有关。

FOXP3阳性调节性T细胞（Tregs）的功能异常可能在包括1型糖尿病（T1D）在内的多种自身免疫性疾病的发病机理中起主要作用。目前尚不清楚与自身免疫性疾病风险相关的遗传多态性是否会影响Treg频率或功能。在这里，我们分析了与T1D相关的主要HLA II类单倍型和六个非HLA基因[INS（rs689），PTPN22（rs2476601），IL2RA（rs12722495和rs2104286），PTPN2（rs45450798），CTLA4的七个单核苷酸多态性的影响（rs3087243）和ERBB3（rs2292239）]。这些是通过流式细胞术在65位进展为T1D的受试者，86位胰岛自身抗体阳性的高风险受试者和215位胰岛自身抗体阴性的健康对照中确定的。PTPN22 rs2476601风险等位基因A与CD4 + CD25 + CD127lowFOXP3 + Treg频率的总数（p = 6×10-6）和幼稚（p = 4×10-5）增加有关。这些发现在一个单独的队列中得到了验证，该队列包含十个三重健康胰岛自身抗体阴性儿童，分别携带三种PTPN22 rs2476601基因型AA，AG和GG（纯Treg分别为p = 0.005和p = 0.03）。总之，我们的分析牵涉到自身免疫性PTPN22 rs2476601风险等位基因A在控制人外周血中Treg的频率。总计为005，初始Treg则为p = 0.03）。总之，我们的分析牵涉到自身免疫性PTPN22 rs2476601风险等位基因A在控制人外周血中Treg的频率。总计为005，初始Treg则为p = 0.03）。总之，我们的分析牵涉到自身免疫性PTPN22 rs2476601风险等位基因A在控制人外周血中Treg的频率。