Tran Paul Mh, Purohit Sharad, Kim Eileen, Bin Satter Khaled, Hopkins Diane, Waugh Kathleen, Dong Fran, Onengut-Gumuscu Suna, Rich Stephen S, Rewers Marian, She Jin-Xiong
Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th Street, Augusta, GA, 30912, USA.
Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University 1120 15th Street, Augusta, GA, 30912, USA.
J Transl Autoimmun. 2021 Oct 16;4:100127. doi: 10.1016/j.jtauto.2021.100127. eCollection 2021.
Multiple cross-sectional and longitudinal studies have shown that serum levels of the chemokine ligand 2 (CCL-2) are associated with type 1 diabetes (T1D), although the direction of effect differs. We assessed CCL-2 serum levels in a longitudinal cohort to clarify this association, combined with genetic data to elucidate the regulatory role of CCL-2 in T1D pathogenesis. The Diabetes Autoimmunity Study in the Young (DAISY) followed 310 subjects with high risk of developing T1D. Of these, 42 became persistently seropositive for islet autoantibodies but did not develop T1D (non-progressors); 48 did develop T1D (progressors). CCL-2 serum levels among the three study groups were compared using linear mixed models adjusting for age, sex, HLA genotype, and family history of T1D. Summary statistics were obtained from the CCL-2 protein quantitative trait loci (pQTL) and expression QTL (eQTL) studies. The T1D fine mapping association data were provided by the Type 1 Diabetes Genetics Consortium (T1DGC). Serum CCL-2 levels were significantly lower in both progressors (p = 0.004) and non-progressors (p = 0.005), compared to controls. Two SNPs (rs1799988 and rs746492) in the 3p21.31 genetic locus, which includes the CCL-2 receptor, , were associated with increased expression (p = 8.2e-5 and 5.2e-5, respectively), decreased CCL-2 serum level (p = 2.41e-9 and 6.21e-9, respectively), and increased risk of T1D (p = 7.9e-5 and 7.9e-5, respectively). The 3p21.31 genetic region is associated with developing T1D through regulatory control of the CCR2/CCL2 immune pathway.
多项横断面和纵向研究表明，趋化因子配体2（CCL-2）的血清水平与1型糖尿病（T1D）相关，尽管其作用方向有所不同。我们在一个纵向队列中评估了CCL-2血清水平，以阐明这种关联，并结合基因数据来阐明CCL-2在T1D发病机制中的调节作用。青少年糖尿病自身免疫研究（DAISY）对310名有发展为T1D高风险的受试者进行了跟踪研究。其中，42人胰岛自身抗体持续呈血清阳性，但未发展为T1D（非进展者）；48人确实发展为T1D（进展者）。使用线性混合模型对年龄、性别、HLA基因型和T1D家族史进行校正，比较了三个研究组之间的CCL-2血清水平。汇总统计数据来自CCL-2蛋白质数量性状位点（pQTL）和表达数量性状位点（eQTL）研究。1型糖尿病精细定位关联数据由1型糖尿病遗传联盟（T1DGC）提供。与对照组相比，进展者（p = 0.004）和非进展者（p = 0.005）的血清CCL-2水平均显著降低。位于3p21.31基因座（其中包括CCL-2受体）的两个单核苷酸多态性（SNP，rs1799988和rs746492）与表达增加（分别为p = 8.2×10^-5和5.2×10^-5）、CCL-2血清水平降低（分别为p = 2.41×10^-9和6.21×10^-9）以及T1D风险增加（分别为p = 7.9×10^-5和7.9×10^-5）相关。3p21.31基因区域通过对CCR2/CCL2免疫途径的调控控制与T1D的发生发展相关。
