A declining first-phase insulin response (FPIR) is associated with positivity for multiple islet autoantibodies, irrespective of class II HLA DR-DQ genotype. We examined the associations of FPIR with genetic variants outside the HLA DR-DQ region in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study in children with and without multiple autoantibodies. Association between FPIR and class I alleles A*24 and B*39 and eight single nucleotide polymorphisms outside the HLA region were analyzed in 438 children who had one or more FPIR results available after seroconversion. Hierarchical linear mixed models were used to analyze repeated measurements of FPIR. In children with multiple autoantibodies, the change in FPIR over time was significantly different between those with various PTPN2 (rs45450798), FUT2 (rs601338), CTSH (rs3825932), and IKZF4 (rs1701704) genotypes in at least one of the models. In general, children carrying susceptibility alleles for type 1 diabetes experienced a more rapid decline in insulin secretion compared with children without susceptibility alleles. The presence of the class I HLA A*24 allele was also associated with a steeper decline of FPIR over time in children with multiple autoantibodies. Certain genetic variants outside the class II HLA region may have a significant impact on the longitudinal pattern of FPIR.

中文翻译：

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具有多种自身抗体的儿童的第一阶段胰岛素反应的纵向模式与 II 类 HLA 区域外的遗传变异相关

下降的第一相胰岛素反应 (FPIR) 与多种胰岛自身抗体的阳性相关，无论 II 类 HLA DR-DQ 基因型如何。我们在芬兰 1 型糖尿病预测和预防 (DIPP) 研究中，研究了 FPIR 与 HLA DR-DQ 区域外遗传变异的关联，研究对象为有和没有多种自身抗体的儿童。FPIR 与 I 类等位基因 A*24 和 B*39 之间的关联以及 HLA 区域外的 8 个单核苷酸多态性在 438 名在血清转换后获得一个或多个 FPIR 结果的儿童中进行了分析。分层线性混合模型用于分析 FPIR 的重复测量。在具有多种自身抗体的儿童中，具有不同 PTPN2 (rs45450798)、FUT2 (rs601338)、CTSH (rs3825932)、和 IKZF4 (rs1701704) 基因型在至少一个模型中。一般来说，与没有易感性等位基因的儿童相比，携带 1 型糖尿病易感性等位基因的儿童的胰岛素分泌下降更快。在具有多种自身抗体的儿童中，I 类 HLA A*24 等位基因的存在也与 FPIR 随着时间的推移急剧下降有关。II 类 HLA 区域之外的某些遗传变异可能对 FPIR 的纵向模式有重大影响。在具有多种自身抗体的儿童中，I 类 HLA A*24 等位基因的存在也与 FPIR 随着时间的推移急剧下降有关。II 类 HLA 区域之外的某些遗传变异可能对 FPIR 的纵向模式产生重大影响。在具有多种自身抗体的儿童中，I 类 HLA A*24 等位基因的存在也与 FPIR 随着时间的推移急剧下降有关。II 类 HLA 区域之外的某些遗传变异可能对 FPIR 的纵向模式产生重大影响。