Functional mechanisms for diabetic nephropathy-associated genetic variants

Abstract

Diabetic nephropathy (DN) is one of the major complications of diabetes. A tremendous amount of genetic variations have been identified to be associated with DN. However, most of them only generate from statistical associations at the DNA level, generally without direct functional evidence regarding their association mechanisms underlying DN. Based on the publicly available datasets and resources, this study performed integrative analyses (expression quantitative trait loci analysis, differential gene expression analysis and functional prediction analysis) to detect the molecular functional mechanisms underlying the associations for DN. Among 150 selected (P \ E-4) genetic associations that were archived in the public databases, two single nucleotide polymorphisms (SNPs) (rs3135377 and rs9469220) have been found to act as cis-effect regulators of the ''identified'' gene (HLA-DRA and HLA-DRB1). These eQTL genes have differential expression signals in the DN-associated cell groups. These SNPs were predicted as regulatory sites by utilizing online prediction tools. Our data suggest potential mechanistic links underlying the association between DN and two identified SNPs. These results could help us to have a deeper understanding of the functional relevance of genetic variants with susceptibility to DN, which is useful for pursuit of in-depth validation studies to dissect their involvements and molecular functional mechanisms in DN.

Long non-coding RNA lncMGC mediates the expression of TGF-β-induced genes in renal cells via nucleosome remodelers

“…Genes associated with kidney fibrosis, such as Col4a3, Col4a4, Nkd2 ( Kuppe et al, 2021 ), Cadm1 ( Hagiyama et al, 2019 ), and Klhl1 , showed similar trends ( Figures 5D–H ). Differentially expressed genes (upregulated by TGF-β but downregulated in KO5 MMC), such as Xylt1 ( Tziastoudi et al, 2020 ), Pcsk5 ( Petra et al, 2022 ), and Ap1s2 ( Woroniecka et al, 2011 ; Zhong et al, 2013 ; Gong et al, 2016 ), also showed similar patterns in ATAC and H3K27ac ( Supplementary Figure S7 ). Nlrx1 (related to mitochondrial immunity and inflammation) ( Moore et al, 2008 ; Tattoli et al, 2008 ; Arnoult et al, 2009 ; Nagai-Singer et al, 2019 ) showed significantly lower expression and ATAC-peaks in KO5 MMC ( Supplementary Figure S8 ).…”

Translational genomics for human diseases: toward a new era of precision medicine

“…DN affects *30 % of patients with long-standing diabetes, and the prevalence of DN is increasing continuously, posing a major challenge to the health-care system in modern society (Ahn et al 2014). One research article was included in this special issue on the functional mechanisms of DNassociated genetic variants (Gong et al 2016). Gong and colleagues reported two single-nucleotide polymorphisms (SNPs) (rs3135377 and rs 9469220) that act as cis-effect regulators of the gene identified for DN by conducting integrative analyses (comprising expression analysis of quantitative-trait loci, differential gene-expression analysis, and functional prediction analysis) using a publicly available dataset.…”