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

Background: Glycogen Storage Disease (GSD) Types Ia and Ib are rare metabolic diseases caused by gene variants in G6PC1 and SLC37A4, respectively. Although life-threatening fasting hypoglycemia can be controlled by a strict diet, patients often suffer from multiple metabolic abnormalities and severe long-term complications. However, the underlying mechanisms remain incompletely understood, and there is a lack of effective monitoring biomarkers. Therefore, the aims of this study are to investigate the pathological mechanisms of the disease and disease complications in GSD I and identify potential protein biomarkers. 

Methods: Comprehensive untargeted proteomics was performed on 18 GSD Ia and 8 GSD Ib sera samples from patients with 21 matched control sera, complemented by liver 3 GSD Ia samples and 1 GSD Ib sample from patient liver tissues, compared to 10 donor liver samples. 

Results: We identified 415 proteins in total. Significantly changed (FDR < 0.05) were observed in 158 (38%) proteins for GSD Ia vs Control, 116 (28%) for GSD Ib vs. Control, and 151 (36%) for GSD Ia vs. Ib. Pathway analysis revealed distinct alterations in serum/plasma, with 58, 32, and 29 significantly changed biological processes (FDR < 0.05) in these three comparisons, respectively. The coagulation pathway was the most significantly changed one in the GSD Ia patients. Immune response-associated proteins, especially immunoglobulins, were 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 and in the liver tissue were identified specifically for monitoring GSD I subtypes and prognosing liver deterioration, namely APOC1 and CD5L to distinguish between GSD Ia and Ib and ALDOB for the presence of hepatocellular carcinoma (HCC) in GSD Ia patients. 

Conclusions: These findings provide new insights into the differences between the two GSD I subtypes and the pathogenesis of GSD I-related complications, as well as highlighting the potential of protein circulating biomarkers for monitoring complication progression in GSD I and assessing HCC risk in GSD Ia patients.