Association of UBE3C Variants with Reduced Kidney Function in Patients with Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM) and the most common variant of end-stage renal disease (ESRD) globally. The economic burden of ESRD treatment with dialysis is substantial. The incidence and prevalence of ESRD in Taiwan remain the highest worldwide. Therefore, identifying genetic factors affecting kidney function would have valuable clinical implications. We performed microarray experiments and identified that ubiquitin protein ligase E3C (UBE3C) is differentially expressed in two DKD patient groups with extreme (low and high) urine protein-to-creatinine ratios. A follow-up genotyping study was performed in a larger group to investigate any specific variants of UBE3C associated with DKD. A total of 263 patients were included in the study, comprising 172 patients with DKD and 91 control subjects (patients with DM without chronic kidney disease (CKD)). Two UBE3C variants (rs3802129(AA) and rs7807(CC)) were determined to be associated with reduced kidney function. The haplotype analysis revealed that rs3802129/rs3815217 (block 1) with A/G haplotype and rs8101/rs7807 (block 2) with T/C haplotype were associated with higher risks of CKD phenotypes. These findings suggest a clinical role of UBE3C variants in DKD risk.

CUL3 induces mitochondrial dysfunction via MRPL12 ubiquitination in renal tubular epithelial cells

“…For instance, ubiquitin ligase E3C (UBE3C) is differentially expressed in DKD patients and diabetes patients without chronic kidney disease. One study intends to illustrate that UBE3C can reduce renal function in DKD patients [28]. In addition, Arkadia was significantly increased in diabetic kidneys and induced Smad7 ubiquitination degradation, which suggested that inactivation of the Arkadia-Smad7 ubiquitin-proteasomal degradation pathway may be a key mechanism [29][30][31].…”

Advances in Personalized Medicines along with Functional Genomics and Pharmacogenomics

“…This Special Issue, Functional Genomics and Pharmacogenomics in Human Disease, covers 15 publications conducted by various groups, including nine original research papers, five review papers, and one case report. Original research papers consist of genetic discovery and functional characterization of CYP1A2 and CYP2C9 [ 1 , 2 ], genetic studies of oral cancer [ 3 , 4 , 5 ], chronic obstruction pulmonary disease (COPD) [ 6 ], asthma [ 7 ], diabetic kidney disease [ 8 ], and web-based pharmacogenomics tool development [ 9 ]. Review papers include the thiopurine treatments with NUDT15 polymorphisms [ 10 ], lipid lowering therapies in familial hypercholesterolemia [ 11 ], incorporation of genetic addiction risk severity (GARS) to overcome the addiction pandemic [ 12 ], and the latest update on genetic variants of UGT [ 13 ] and SULT genes [ 14 ].…”

“…Diabetic kidney disease (DKD) occurs mainly in diabetic mellitus patients and is the most common form of end-stage renal disease (ERSD). A microarray experiment was conducted and found that the ubiquitin protein ligase E3C (UBE3C) is a candidate gene that affects kidney function [ 8 ]. Then, it was reported that the UBE3C haplotype with the identified variants was correlated with chronic kidney disease.…”