Identification of novel genomic variants in diabetic nephropathy patients using whole-exome sequencing: a pilot...

Type 2 diabetes (T2D) is a challenge for the healthcare system. It is a metabolic disease with increased blood sugar with severe complications when it becomes uncontrolled. These complications include diabetic nephropathy (DN), neuropathy, retinopathy neuropathy, and cardiovascular diseases (CVDs). T2D is induced by genetic, environmental, and lifestyle risk factors. Therefore, it is vital to distinguish between genetic risk loci for T2D and those that specifically predispose patients to DN, which may eventually facilitate personalized risk assessment and informed genetic counseling once these markers are clinically validated. The aim of this pilot study was to examine the candidate genes associated with DN using whole-exome sequencing (WES).

We examined the relationship between specific genetic variations and DN in 26 (eight female and 18 male patients) clinically diagnosed DN patients in Tabuk. We utilized WES which was performed on the Illumina NovaSeq 6000 platform. Data were analyzed using an array of bioinformatic tools including FASTQC, Trimmomatic, Ensemble, Bowtie2, GATK, SAMtools, Python Comut, T2Diacod, StringDB, Gene Ontology, and KEGG.

The genes THADA, NOTCH4, and TNXB met the genome-wide threshold and showed minimal T2D association. The DN-specific genes including SP2, CDH3, and ARFGEF2 met the suggestive DN threshold, however falling below the T2D significance. The shared genes, INSR, HLA-DQB1, and CRHR1, exhibited possible associations with T2D and DN, positioning them as key candidates for DN. Pathways and biological processes potentially affected by these gene variations include inflammatory pathway, lipid and glucose metabolism, PI3K-Akt signaling, insulin signaling, AMPK signaling pathways, and others. Moreover, we identified putative novel missense variations in the genes SRCAP, PHKG2, TNFRSF6B, and PBX2.

Our exploratory study identified candidate novel variations in the SRCAP, PHKG2, TNFRSF6B, and PBX2 genes that may be linked to DN. These results indicate that these genes are potentially involved in DN development. Nevertheless, further verifications through large-scale cohorts and functional protein studies are required to determine the clinical utility of these variants as potential biomarkers.