HbA1c is associated with altered expression in blood of cell cycle- and immune response-related genes

Individuals with type 2 diabetes are heterogeneous in their glycaemic control as tracked by blood HbA(1c) levels. Here, we investigated the extent to which gene expression levels in blood reflect current and future HbA(1c) levels. HbA(1c) 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 HbA(1c) in the target tissues, muscle and pancreas. At baseline, 220 genes (1.4%) were associated with baseline HbA(1c). 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 HbA(1c) and nine genes (0.06%) with 2 year HbA(1c). Five genes overlapped across all time points, and 18 additional genes between baseline and 1 year follow-up. After adjustment for baseline HbA(1c), 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. HbA(1c) levels in individuals with type 2 diabetes are associated with expression levels of genes that link to the cell cycle and complement system activation.