Hu Xiaowei, Webb-Robertson Bobbie-Jo M, Parikh Hemang M, Nakayasu Ernesto S, Onengut-Gumuscu Suna, Chen Wei-Min, Frazer-Abel Ashley, Metz Thomas O, Rich Stephen S, Rewers Marian J, Manichaikul Ani
Department of Genome Sciences, University of Virginia.
Biological Sciences Division, Pacific Northwest National Laboratory.
Res Sq. 2025 Feb 10:rs.3.rs-5975824. doi: 10.21203/rs.3.rs-5975824/v1.
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of the insulin-producing beta cells, and there is no cure yet for the disease. While islet autoantibodies are well-recognized biomarkers that mark the onset of islet autoimmunity (IA) and are predictors of T1D, few additional biomarkers are available to monitor disease progression. Recent studies have reported the involvement of complement system proteins in the initiation and progression of IA in the study of T1D. However, the genetic factors of complement system proteins at the time of triggering of IA is unknown.
Through complement system protein quantitative trait locus (pQTL) mapping analysis of 170 participants from the Diabetes Autoimmunity Study in the Young (DAISY), we identified 240 statistically significant pQTLs (false discovery rate, FDR < 0.1) from pooled and IA case-stratified analyses. Replication analysis conducted on 385 IA cases from The Environment Determinants of Diabetes in the Young (TEDDY) study confirmed 68 significant (FDR < 0.05) pQTLs in total for C8A, C8B, CFB, C4A, and MBL2. Furthermore, all replicated pQTLs of CFB and C4A were previously reported to be associated with T1D risk.
We identified and replicated 68 pQTLs for five complement system proteins (C8A, C8B, CFB, C4A, and MBL2) in the young population. Among them, all replicated pQTLs of CFB and C4A are also associated with T1D risk. Our study provides evidence of complement system proteins as potential protein biomarkers underlying the development and progression of T1D.
1型糖尿病（T1D）的特征是产生胰岛素的β细胞发生自身免疫性破坏，目前该疾病尚无治愈方法。胰岛自身抗体是公认的生物标志物，可标记胰岛自身免疫（IA）的发病并预测T1D，但几乎没有其他生物标志物可用于监测疾病进展。最近的研究报告了补体系统蛋白在T1D研究中IA的起始和进展中的作用。然而，IA触发时补体系统蛋白的遗传因素尚不清楚。
通过对青少年糖尿病自身免疫研究（DAISY）的170名参与者进行补体系统蛋白数量性状位点（pQTL）定位分析，我们从汇总分析和IA病例分层分析中确定了240个具有统计学意义的pQTL（错误发现率，FDR < 0.1）。对青少年糖尿病环境决定因素（TEDDY）研究中的385例IA病例进行的重复分析共确认了C8A、C8B、CFB、C4A和MBL2的68个显著（FDR < 0.05）pQTL。此外，CFB和C4A的所有重复pQTL先前都被报道与T1D风险相关。
我们在年轻人群中鉴定并重复了五种补体系统蛋白（C8A、C8B、CFB、C4A和MBL2）的68个pQTL。其中，CFB和C4A的所有重复pQTL也与T1D风险相关。我们的研究提供了证据，表明补体系统蛋白是T1D发生和发展的潜在蛋白质生物标志物。
