Genetic Variants and Their Associations to Type 2 Diabetes Mellitus Complications in the United Arab Emirates

Abstract

Aim: Type 2 Diabetes Mellitus (T2DM) is associated with microvascular complications, including diabetic retinopathy (DR), diabetic nephropathy (DNp), and diabetic peripheral neuropathy (DPN). In this study, we investigated genetic variations and Single Nucleotide Polymorphisms (SNPs) associated with DR, DNp, DPN and their combinations among T2DM patients of Arab origin from the United Arab Emirates, to establish the role of genes in the progression of microvascular diabetes complications.

Methods: A total of 158 Emirati patients with T2DM were recruited in this study. The study population was divided into 8 groups based on the presence of single, dual, or all three complications. SNPs were selected for association analyses through a search of publicly available databases, specifically genome-wide association study (GWAS) catalog, infinome genome interpretation platform, and GWAS Central database. A multivariate logistic regression analysis and association test were performed to evaluate the association between 83 SNPs and DR, DNp, DPN, and their combinations.

Results: Eighty-three SNPs were identified as being associated with T2DM and 18 SNPs had significant associations to one or more diabetes complications. The most strongly significant association for DR was rs3024997 SNP in the VEGFA gene. The top-ranked SNP for DPN was rs4496877 in the NOS3 gene. A trend towards association was detected at rs833068 and rs3024998 in the VEGFA gene with DR and rs743507 and rs1808593 in the NOS3 gene with DNp. For dual complications, the rs833061, rs833068 and rs3024997 in the VEGFA gene and the rs4149263 SNP in the ABCA1 gene were also with borderline association with DR/DNp and DPN/DNp, respectively. Diabetic with all of the complications was significantly associated with rs2230806 in the ABCA1 gene. In addition, the highly associated SNPs rs3024997 of the VEGFA gene and rs4496877 of the NOS3 gene were linked to DR and DPN after adjusting for the effects of other associated markers, respectively.

Conclusions: The present study reports associations of different genetic polymorphisms with microvascular complications and their combinations in Emirati T2DM patients, reporting new associations, and corroborating previous findings. Of interest is that some SNPs/genes were only present if multiple comorbidities were present and not associated with any single complication.

Keywords: Arab population; United Arab Emirates; microvascular complication; nephropathy; peripheral neuropathy; retinopathy; single nucleotide polymorphism; type 2 diabetes mellitus.

Figure 1

Diagram showing the genes associated with the different complications, highlighting which area of the human body they affect. DPN, diabetic peripheral neuropathy; DNp, diabetic nephropathy; DR, diabetic retinopathy; DPN/DNp, diabetic peripheral neuropathy and nephropathy; DR/DPN, diabetic retinopathy and peripheral neuropathy, DR/DNp, diabetic retinopathy and nephropathy; DR/DPN/DNp, diabetic retinopathy, peripheral neuropathy and nephropathy. SLC2A1, Solute Carrier Family 2 Member 1; VEGFA, Vascular endothelial growth factor A; NOS3, Nitric Oxide Synthase 3; ABCA1, ATP Binding Cassette Subfamily A Member 1; TGFB1, Transforming Growth Factor Beta 1; COMT, Catechol-O-methyltransferase. Created with BioRender.com.

Figure 2

Illustrative figure summarizing the role each of gene and potential complications. SLC2A1, Solute Carrier Family 2 Member 1; VEGFA, Vascular endothelial growth factor A; NOS3, Nitric Oxide Synthase 3; ABCA1, ATP Binding Cassette Subfamily A Member 1; TGFB1, Transforming Growth Factor Beta 1; COMT, Catechol-O-methyltransferase. Created with BioRender.com.

Figure 3

Constructed interaction networks including all the genes related to the top SNPs associated with diabetic complications in this study. Black circles indicate the queried genes. Green lines represent the genetic interactions. Blue lines represent the protein-protein interaction.