Identified genetic loci for C-peptide and age at diagnosis (AAD) in individuals with type 1 diabetes (T1D) explain only a small proportion of their variation. Here, we aimed to perform large metagenome-wide association studies (GWAS) of C-peptide and AAD in T1D; and to identify the HLA allele/haplotypes associated with C-peptide and AAD. 7,252 and 7,923 European individuals with T1D were included in C-peptide and AAD GWAS, respectively. HLA-DQB1*06:02 which is strongly protective against T1D was associated with higher C-peptide. HLA-DQB1*03:02, HLADRB1*03:01 and HLA-A*24:02 which increase T1D risk were independently associated with younger AAD. HLA-DR3-DR4 haplotype combination, the strongest T1D susceptibility factor, was associated with younger AAD. Outside HLA region, rs115673528 on Chr5 (GABRG2) was associated with C-peptide, and an indel, rs111970692, on Chr15 within CTSH, a known T1D locus, was associated with AAD. Genetically predicted CTSH expression, methylation and protein levels were associated with AAD; Mendelian randomization analysis suggested that higher levels of procathepsin H reduce AAD. In conclusion, some HLA allele/haplotypes associated with T1D also contribute to variability of C-peptide and AAD. Outside HLA, T1D loci are generally not associated with C-peptide or AAD. CTSH could be a potential therapeutic target to delay development/progression of type 1 diabetes.

中文翻译：

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C 肽的遗传学和 1 型糖尿病的诊断年龄


在 1 型糖尿病 （T1D） 患者中确定的 C 肽遗传位点和诊断年龄 （AAD） 仅解释了其变异的一小部分。在这里，我们旨在对 T1D 中的 C 肽和 AAD 进行大型宏基因组范围关联研究 （GWAS）;并识别与 C 肽和 AAD 相关的 HLA 等位基因/单倍型。7,252 例和 7,923 例欧洲 T1D 个体分别被纳入 C 肽和 AAD GWAS。HLA-DQB1*06：02 对 T1D 具有很强的保护作用，与较高的 C 肽相关。增加 T1D 风险的 HLA-DQB1*03：02、HLADRB1*03：01 和 HLA-A*24：02 与较年轻的 AAD 独立相关。HLA-DR3-DR4 单倍型组合是最强的 T1D 易感因素，与较年轻的 AAD 相关。在 HLA 区域之外，Chr5 （GABRG2） 上的 rs115673528 与 C 肽相关，而 CTSH 内 Chr15 上的插入缺失 rs111970692（一个已知的 T1D 基因座）与 AAD 相关。基因预测的 CTSH 表达、甲基化和蛋白水平与 AAD 相关;孟德尔随机化分析表明，更高水平的 procathepsin H 可降低 AAD。总之，一些与 T1D 相关的 HLA 等位基因/单倍型也有助于 C 肽和 AAD 的变异性。在 HLA 之外，T1D 位点通常与 C 肽或 AAD 无关。CTSH 可能是延缓 1 型糖尿病发展/进展的潜在治疗靶点。