HbA1c is associated with altered expression in blood of cell cycle- and immune response-related genes
Roderick C Slieker1,2, Amber A W A van der Heijden3, Nienke van Leeuwen1
1Department of Molecular Cell Biology, Leiden University Medical Center, Postal Box 9600, 2300 RC, Leiden, the Netherlands.
Insights
Gene expression in blood reflects current, but not future, blood sugar (HbA1c) levels in type 2 diabetes patients. Key genes involved in cell cycle and complement pathways are linked to glycemic control.
Area of Science:
- Genomics
- Metabolic Diseases
- Molecular Biology
Background:
- Individuals with type 2 diabetes exhibit varied glycemic control, measured by hemoglobin A1c (HbA1c).
- Understanding the relationship between gene expression and HbA1c is crucial for personalized diabetes management.
Purpose of the Study:
- To investigate the correlation between blood gene expression levels and current/future HbA1c in type 2 diabetes.
- To identify specific genes and pathways associated with HbA1c levels.
Main Methods:
- RNA sequencing was performed on blood samples from 391 type 2 diabetes patients.
- HbA1c levels were measured at baseline and at 1 and 2-year follow-ups.
- Pathway enrichment analysis and cross-tissue validation (muscle, pancreas) were conducted.
Main Results:
- At baseline, 220 genes (1.4%) correlated with HbA1c, enriched in cell cycle and complement pathways.
- Fifteen genes showed cross-tissue associations in muscle and pancreatic islets.
- Follow-up analysis revealed fewer gene associations, suggesting blood gene expression reflects current, not future, glycemic status.
Conclusions:
- Blood gene expression is significantly associated with current HbA1c levels in type 2 diabetes.
- Identified genes are involved in cell cycle regulation and immune responses (complement system).
- The findings highlight the dynamic relationship between gene expression and glycemic control over time.
Aims/Hypothesis:
Individuals with type 2 diabetes are heterogeneous in their glycaemic control as tracked by blood HbA1c levels. Here, we investigated the extent to which gene expression levels in blood reflect current and future HbA1c levels.
Methods:
HbA1c levels at baseline and 1 and 2 year follow-up were compared with gene expression levels in 391 individuals with type 2 diabetes from the Hoorn Diabetes Care System Cohort (15,564 genes, RNA sequencing). The functions of associated baseline genes were investigated further using pathway enrichment analysis. Using publicly available data, we investigated whether the genes identified are also associated with HbA1c in the target tissues, muscle and pancreas.
Results:
At baseline, 220 genes (1.4%) were associated with baseline HbA1c. Identified genes were enriched for cell cycle and complement system activation pathways. The association of 15 genes extended to the target tissues, muscle (n = 113) and pancreatic islets (n = 115). At follow-up, expression of 25 genes (0.16%) associated with 1 year HbA1c and nine genes (0.06%) with 2 year HbA1c. Five genes overlapped across all time points, and 18 additional genes between baseline and 1 year follow-up. After adjustment for baseline HbA1c, the number of significant genes at 1 and 2 years markedly decreased, suggesting that gene expression levels in whole blood reflect the current glycaemic state and but not necessarily the future glycaemic state.
Conclusions/Interpretation:
HbA1c levels in individuals with type 2 diabetes are associated with expression levels of genes that link to the cell cycle and complement system activation.
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