Whole Exome Sequencing in 26 Saudi Patients Expands the Mutational and Clinical Spectrum of Diabetic Nephropathy

Abstract

Background and Objectives: Type 2 diabetes mellitus (T2DM) is a health problem all over the world due to its serious complications such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular diseases, and limb amputation. The risk factors for T2DM are environmental, lifestyle, and genetic. The genome-wide association studies (GWASs) have revealed the linkage of certain loci with diabetes mellitus (DM) and its complications. The objective of this study was to examine the association of genetic loci with diabetic nephropathy (DN) in the Saudi population. Materials and Methods: Whole exome sequencing (WES) and bioinformatics analysis, such as Genome Analysis Toolkit, Samtools, SnpEff, Polymorphism Phenotyping v2, and Sorting Intolerant from Tolerant (SIFT), were used to examine the association of gene variations with DN in 26 Saudi patients (18 males and 8 females). Results: The present study showed that there are loci that are probably linked to DM and DN. The genes showed variations that include COCH, PRPF31, PIEZO2, RABL5, CCT5, PLIN3, PDE4A, SH3BP2, GPR108, GPR108, MUC6, CACNA1D, and MAFA. The physiological processes that are potentially affected by these gene variations include insulin signaling and secretion, the inflammatory pathway, and mitochondrial function. Conclusion: The variations in these genes and the dysregulation of these processes may be linked to the development of DM and DN. These findings require further verification in future studies with larger sample sizes and protein functional studies. The results of this study will assist in identifying the genes involved in DM and DN (for example, through genetic counseling) and help in prevention and treatment of individuals or populations at risk of this disease and its complications.

Keywords: bioinformatics; diabetes complications; diabetes mellitus (DM); diabetic nephropathy (DN); type 2 diabetes mellitus (T2DM); whole exome sequencing (WES).

Figure 1

Chromosomal distribution of SNPs in T2DM patients. Distribution of identified SNPs across different chromosomes in the T2DM and nephropathy study populations. Chromosome 19 harbored the highest SNP count, while chromosomes 20, 21, 22, and X were found to have fewer variants. This distribution presumably represents the genomic regions associated with susceptibility to T2DM and progression to diabetic nephropathy.

Figure 2

PolyPhen-2 predictions for SNPs identified in T2DM patients. The classified SNPs were predicted to have one of three impacts on their protein function: benign, possibly damaging, or probably damaging.

Figure 3

SIFT score distribution for SNPs in T2DM patients. Variants were classified as “tolerated” or “deleterious” based on their functional impact.

Figure 4

Key genes associated with T2DM pathophysiology and insulin resistance. Pictorially representing genes in this study implicated in T2DM. Genes highlighted in red with a red box outline indicate those with identified mutations, while genes in red with a black box outline represent genes affected by the mutated genes.