Identification of novel differentially expressed genes in type 1 diabetes mellitus complications using transcriptomic profiling of UAE patients: a multicenter study

Abstract

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disorder that mainly affects children and young adults. It is associated with debilitating and long-life complications. Therefore, understanding the factors that lead to the onset and development of these complications is crucial. To our knowledge this is the first study that attempts to identify the common differentially expressed genes (DEGs) in T1DM complications using whole transcriptomic profiling in United Arab Emirates (UAE) patients. The present multicenter study was conducted in different hospitals in UAE including University Hospital Sharjah, Dubai Hospital and Rashid Hospital. A total of fifty-eight Emirati participants aged above 18 years and with a BMI < 25 kg/m² were recruited and forty-five of these participants had a confirmed diagnosis of T1DM. Five groups of complications associated with the latter were identified including hyperlipidemia, neuropathy, ketoacidosis, hypothyroidism and polycystic ovary syndrome (PCOS). A comprehensive whole transcriptomic analysis using NGS was conducted. The outcomes of the study revealed the common DEGs between T1DM without complications and T1DM with different complications. The results revealed seven common candidate DEGs, SPINK9, TRDN, PVRL4, MYO3A, PDLIM1, KIAA1614 and GRP were upregulated in T1DM complications with significant increase in expression of SPINK9 (Fold change: 5.28, 3.79, 5.20, 3.79, 5.20) and MYO3A (Fold change: 4.14, 6.11, 2.60, 4.33, 4.49) in hyperlipidemia, neuropathy, ketoacidosis, hypothyroidism and PCOS, respectively. In addition, functional pathways of ion transport, mineral absorption and cytosolic calcium concentration were involved in regulation of candidate upregulated genes related to neuropathy, ketoacidosis and PCOS, respectively. The findings of this study represent a novel reference warranting further studies to shed light on the causative genetic factors that are involved in the onset and development of T1DM complications.

Figure 1

Heat map of overlapping differentially expressed genes as identified by ANOVA and eBayes analysis of healthy controls, T1DM with no complications and T1DM with complication groups. Red color represents upregulated genes whereas blue color represents downregulated genes. Color scale is shown on the top left corner of the figure. Ctrl control, HyperL Hyperlipidemia, NeuroP Neuropathy, Ketoacid Ketoacidosis, HypoTH Hypothyroidism, PCOS Polycystic Ovarian Syndrome.

Figure 2

Upregulated and common DEGs between the T1DM without complications (blue circles) and T1DM with complication groups (yellow circles; (A) Hyperlipidemia, (B) Neuropathy, (C) Ketoacidosis, (D) Hypothyroidism and (E) Polycystic Ovarian Syndrome [PCOS]). Overlap between the two circles denotes the number and corresponding percentage of the common genes which was highest between T1DM without complications vs T1DM with hyperlipidemia (23.8%) and lowest for the PCOS group (12.5%).

Figure 3

Enriched pathways and functional clusters of upregulated common genes between DWC vs T1DM with complication groups ((A) Hyperlipidemia, (B) Neuropathy, (C) Ketoacidosis, (D) Hypothyroidism and (E) Polycystic Ovarian Syndrome [PCOS]).

Figure 4

Downregulated and common DEGs between the T1DM without complications (blue circles) and T1DM with complication groups (yellow circles); (A) Hyperlipidemia, (B) Neuropathy, (C) Ketoacidosis, (D) Hypothyroidism and (E) Polycystic Ovarian Syndrome [PCOS]). Overlap between the two circles denotes the number and corresponding percentage of the common genes which was highest between T1DM without complications vs T1DM with ketoacidosis (33.2%) and lowest for the neuropathy group (21.1%).

Figure 5

Enriched pathways and functional clusters of downregulated common genes between DWC vs T1DM with complication groups ((A) Hyperlipidemia, (B) Neuropathy, (C) Ketoacidosis, (D) Hypothyroidism and (E) Polycystic Ovarian Syndrome [PCOS]).

Figure 6

Differentially expressed genes common between all complications. A. Upregulated common genes; B. List of the seven upregulated common genes.

Figure 7

ROC curves of common upregulated DEGs between all T1DM complications. (A) ROC curves of upregulated common genes. (B) Area under the ROC curve. ROC receiver operating characteristic.

Figure 8

Boxplots of upregulated and downregulated genes differentially expressed between DWC and T1DM with complications. Fig. (A,B) show corresponding boxplots for the upregulated genes (KIAA1614, TRDN) whereas Fig. (C–K) show corresponding boxplots for the downregulated genes (DPPA5, DNM3OS, PPP1R1B, OR2T6, TCEB3C, OR8H1, IFNA4, OR11H12, OR4K15). Significance was calculated using one-way ANOVA between the DWC group versus the complication groups. P < 0.05 was considered significant (*P < 0.05; **P < 0.01, ***P < 0.001, ****P < 0.0001). DWC T1DM without complication, HL Hyperlipidemia, NP Neuropathy, HT Hypothyroidism, KA Ketoacidosis, PCOS Polycystic Ovarian Syndrome.