Identification of genetic variants associated with diabetic kidney disease in multiple Korean cohorts via a genome-wide association study mega-analysis

Abstract

Background The pathogenesis of diabetic kidney disease (DKD) is complex, involving metabolic and hemodynamic factors. Although DKD has been established as a heritable disorder and several genetic studies have been conducted, the identification of unique genetic variants for DKD is limited by its multiplex classification based on the phenotypes of diabetes mellitus (DM) and chronic kidney disease (CKD). Thus, we aimed to identify the genetic variants related to DKD that differentiate it from type 2 DM and CKD. Methods We conducted a large-scale genome-wide association study mega-analysis, combining Korean multi-cohorts using multinomial logistic regression. A total of 33,879 patients were classified into four groups—normal, DM without CKD, CKD without DM, and DKD—and were further analyzed to identify novel single-nucleotide polymorphisms (SNPs) associated with DKD. Additionally, fine-mapping analysis was conducted to investigate whether the variants of interest contribute to a trait. Conditional analyses adjusting for the effect of type 1 DM (T1D)-associated HLA variants were also performed to remove confounding factors of genetic association with T1D. Moreover, analysis of expression quantitative trait loci (eQTL) was performed using the Genotype-Tissue Expression project. Differentially expressed genes (DEGs) were analyzed using the Gene Expression Omnibus database (GSE30529). The significant eQTL DEGs were used to explore the predicted interaction networks using search tools for the retrieval of interacting genes and proteins. Results We identified three novel SNPs [rs3128852 (P = 8.21×10−25), rs117744700 (P = 8.28×10−10), and rs28366355 (P = 2.04×10−8)] associated with DKD. Moreover, the fine-mapping study validated the causal relationship between rs3128852 and DKD. rs3128852 is an eQTL for TRIM27 in whole blood tissues and HLA-A in adipose-subcutaneous tissues. rs28366355 is an eQTL for HLA-group genes present in most tissues. Conclusions We successfully identified SNPs (rs3128852, rs117744700, and rs28366355) associated with DKD and verified the causal association between rs3128852 and DKD. According to the in silico analysis, TRIM27 and HLA-A can define DKD pathophysiology and are associated with immune response and autophagy. However, further research is necessary to understand the mechanism of immunity and autophagy in the pathophysiology of DKD and to prevent and treat DKD.

Pathomechanisms of Diabetic Kidney Disease

“…Further, in a thorough GWAS study mega-analysis encompassing 33,879 patients, scientists pinpointed particular SNPs (specifically, rs3128852, rs117744700, and rs28366355) linked to DKD. Importantly, they confirmed the causative connection between rs3128852 and the onset of DKD [287]. Through GWAS of the Family Investigation of Nephropathy and Diabetes cohort, we have identified several novel loci associated with albuminuria, eGFR, DM, DKD, advanced DKD, and renal failure [288][289][290][291][292][293].…”

Prevalence of chronic kidney disease in Tunisian diabetics: the TUN-CKDD survey

“…The reasons behind these reported gender disparities in CKD are still largely unknown, but hormonal and genetic differences might be incriminated. Indeed, genetic susceptibility to CKD can be attributed to some identified genes and single nucleotide polymorphisms (SNPs) [ 33 , 34 ]. Moreover, the involvement of epigenetic mechanisms along with their potential interactions with personal or environmental factors including gender, may also exert a significant influence [ 35 , 36 ].…”

Finerenone: From the Mechanism of Action to Clinical Use in Kidney Disease

“…Some new insights have been gleaned regarding the pathophysiology of DKD, recognizing the impact of altered gut microbiota and their metabolites (the so-called gut–kidney axis) on the development of progressive kidney disease in diabetic patients [ 27 ]. Genetic susceptibility to DKD has also been noted [ 28 ]. Figure 1 presents a schematic overview of crucial pathogenetic events in DKD.…”

“…Pharmaceuticals 2024, 17, x FOR PEER REVIEW 3 of 15 kidney axis) on the development of progressive kidney disease in diabetic patients [27]. Genetic susceptibility to DKD has also been noted [28]. Figure 1 presents a schematic overview of crucial pathogenetic events in DKD.…”