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

Abstract

Aims/hypothesis 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. Methods 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.Results 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. Conclusions/interpretation 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.

Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study

“…A limitation of our study is the lack of measured blood cell counts, thus restricting us to the use of estimated white blood cell proportions from the transcriptomics data. However, in a previous study, the same types of estimates were highly correlated with measured cell proportions in external data independent of the training data [29]. Furthermore, in the current study, additional pathway and immune cell-type enrichment analyses corroborated the conclusions derived from using these estimates.…”

“…S5), defined as clusters of internally correlated modules, which as a whole were highly stable (super-module stability estimate > 79%, Additional file 3 : Table S4). As white blood cell (WBC) counts were not available in our data, we estimated WBC proportions per individual from the transcriptomics data as previously described [ 29 ] and investigated whether the relative expression of the genes forming the co-expression modules was reflective of differences in WBC proportions. We observed strong and consistent correlations between two super-modules and estimated neutrophil and lymphocyte levels, respectively (Fig.…”

“…With the prediction model, the estimated cell proportions were computed and compared to the measured cell counts, which were highly correlated. The prediction model was also validated in an independent external dataset [ 29 ], which again showed high correlations with four of the five measured cell counts (neutrophils r = 0.81, lymphocytes r = 0.83, monocytes r = 0.64, eosinophils r = 0.91 and basophils r = 0.08).…”

“…By contrast, largescale transcriptomics studies in the context of prediabetes and T2D are lacking, as transcriptomic studies for T2D have mainly focused on key T2D tissues such as pancreatic islets [16][17][18][19], skeletal muscle [20] and adipose tissue [21] that are not easily accessible, and those focusing on blood have been limited to small cohorts (n < 100) [22][23][24][25][26][27][28]. A recent study described whole blood transcriptomics associations with HbA1c levels in T2D patients [29], but it is still unknown if similar associations exist in people at risk but yet free of diabetes. Thus, the extent to which the transcriptional profiles of whole blood, mainly involving components of the immune system, reflect or contribute to metabolic phenotypes that predispose to T2D remains unclear.…”

Signs of Deregulated Gene Expression Are Present in Both CD14+ and CD14- PBMC From Non-Obese Men With Family History of T2DM

“…Type 2 diabetes mellitus (T2DM) is associated with a number of disturbances of immune status and metabolic pathways ( 1 ) that can be detected not only in insulin sensitive tissue but also in easily accessible peripheral blood mononuclear cells (PBMC). PBMC from patients with T2DM have shown alterations in mRNA levels of genes involved in the regulation of inflammation, lipid and glucose metabolism, and several signaling pathways ( 2 – 5 ). Development of T2DM is based on both environmental and genetic factors.…”