Proteomics profiling of serum and liver in GSD Ia and Ib patients: insights into complication mechanisms and circulation biomarkers

Background: Glycogen Storage Disease (GSD) Type Ia and Ib are rare metabolic diseases caused by gene variants in G6PC and SLC37A4 respectively. Patients often suffer from multiple metabolic abnormalities and severe long-term complications. Methods: In this study, we employed comprehensive untargeted proteomics on retrospectively registered samples: 26 serum/plasma samples (18 GSD Ia and 8 GSD Ib) from patients with 21 matched healthy controls, complemented by 4 liver samples from 3 patients who received liver transplantation (3 from GSD Ia including 1 with hepatocellular carcinoma tissue and 1 from GSD Ib), compared to 10 donor liver samples, to investigate the pathological mechanisms of disease complications and identify potential biomarkers. Results: Pathway analysis of the differentially regulated proteins revealed distinct changes in the serum/plasma of GSD Ia and Ib. Coagulation was the most significantly changed biological process in the GSD Ia patients. Immune response-associated proteins, especially a large number of immunoglobulins, increased in GSD Ib specifically. Proteins related to liver injury, cholesterol, and amyloidosis were altered in two subtypes, though more pronounced in GSD Ia. Potential biomarkers with significant alterations both in the circulation as well as in the liver were identified specifically for monitoring and prognosing GSD Ia (COL163 and PROC), GSD Ib (F11 and CD163), and hepatocellular carcinoma (HCC) in GSD Ia patients (ALDOB and CFHR5). Conclusions: These findings provide new insights into the pathogenesis of GSD I-related complications and highlighted the potential of protein circulating biomarkers for monitoring complication progression in GSD Ia and Ib, as well as for assessing HCC risk in GSD Ia patients.

背景：糖原贮积病（Glycogen Storage Disease, GSD）Ia型与Ib型是分别由G6PC和SLC37A4基因变异引发的罕见代谢疾病，患者常并发多种代谢异常及严重的长期并发症。方法：本研究针对回顾性登记的样本开展全面非靶向蛋白质组学分析：纳入26份血清/血浆样本（18例GSD Ia型患者、8例GSD Ib型患者）及21例匹配的健康对照；同时补充3例接受肝移植患者的4份肝脏样本（3份来自GSD Ia型患者，其中1份为肝细胞癌（hepatocellular carcinoma, HCC）组织，1份来自GSD Ib型患者），并以10份供体肝脏样本作为对照，以探究疾病并发症的病理机制并筛选潜在生物标志物。结果：对差异调控蛋白的通路分析显示，GSD Ia型与Ib型患者的血清/血浆蛋白谱存在显著差异。凝血通路是GSD Ia型患者中改变最显著的生物学过程；而GSD Ib型患者体内与免疫应答相关的蛋白（尤其是大量免疫球蛋白）表达水平显著升高。两种亚型患者均出现与肝损伤、胆固醇代谢及淀粉样变相关的蛋白异常，且该变化在GSD Ia型患者中更为显著。本研究还筛选出仅在循环系统及肝脏组织中均存在显著表达变化的潜在生物标志物：可用于监测与预后评估GSD Ia型患者的COL163与PROC、用于GSD Ib型患者的F11与CD163，以及用于GSD Ia型患者合并肝细胞癌（HCC）的ALDOB与CFHR5。结论：本研究结果为GSD I型相关并发症的发病机制提供了新的见解，并凸显了循环蛋白生物标志物在监测GSD Ia型与Ib型患者并发症进展，以及评估GSD Ia型患者肝细胞癌（HCC）发病风险中的应用潜力。