Combined Genetic Association and Differed Expression Analysis of <i>UBE2L3</i> Uncovers a Genetic Regulatory Role of (Immuno)proteasome in IgA Nephropathy

Xu, Lin-Lin; Gan, Ting; Li, Yang; Chen, Pei Pei; Shi, Su-Fang; Liu, Li-Jun; Lv, Ji-Cheng; Zhang, Hong.; Zhou, Xu-Jie

doi:10.1159/000537987

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Combined Genetic Association and Differed Expression Analysis of UBE2L3 Uncovers a Genetic Regulatory Role of (Immuno)proteasome in IgA Nephropathy

research-article

Author(s): Lin-Lin Xu ^a ^, ^b ^, ^c ^, ^d ^, ^e ^, ^f ^, , Ting Gan ^a ^, ^b ^, ^c ^, ^d ^, ^e ^, ^f , Yang Li ^a ^, ^b ^, ^c ^, ^d ^, ^e ^, ^f , Pei Chen ^a ^, ^b ^, ^c ^, ^d ^, ^e ^, ^f , Su-Fang Shi ^a ^, ^b ^, ^c ^, ^d ^, ^e ^, ^f , Li-Jun Liu ^a ^, ^b ^, ^c ^, ^d ^, ^e ^, ^f , Ji-Cheng Lv ^a ^, ^b ^, ^c ^, ^d ^, ^e ^, ^f , Hong Zhang ^a ^, ^b ^, ^c ^, ^d ^, ^e ^, ^f , Xu-Jie Zhou ^a ^, ^b ^, ^c ^, ^d ^, ^e ^, ^f ^,

Publication date (Electronic): 2 March 2024

Journal: Kidney Diseases

Publisher: S. Karger AG

Keywords: IgA nephropathy, Immunoproteasome, Ubiquitin-conjugating enzyme, Ubiquitin-proteasome system

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Abstract

Introduction

IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the (immuno)proteasome probably plays an important role in IgAN.

Methods

We firstly analyzed the association of variants in the UBE2L3 region with susceptibility to IgAN in 3,495 patients and 9,101 controls, and then analyzed the association between lead variant and clinical phenotypes in 1,803 patients with regular follow-up data. The blood mRNA levels of members of the ubiquitin-proteasome system including UBE2L3 were analyzed in peripheral blood mononuclear cells from 53 patients and 28 healthy controls. The associations between UBE2L3 and the expression levels of genes involved in Gd-IgA1 production were also explored.

Results

The rs131654 showed the most significant association signal in UBE2L3 region (OR: 1.10, 95% CI: 1.04–1.16, p = 2.29 × 10 ⁻³), whose genotypes were also associated with the levels of Gd-IgA1 ( p = 0.04). The rs131654 was observed to exert cis-eQTL effects on UBE2L3 in various tissues and cell types, particularly in immune cell types in multiple databases. The UBE2L3, LUBAC, and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of UBE2L3 were not only associated with higher proteinuria ( r = 0.34, p = 0.01) and lower eGFR ( r = −0.28, p = 0.04), but also positively correlated with the gene expression of LUBAC and other proteasome subunits. Additionally, mRNA expression levels of UBE2L3 were also positively correlated with IL-6 and RELA, but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including C1GALT1 and C1GALT1C1.

Conclusion

In conclusion, by combined genetic association and differed expression analysis of UBE2L3, our data support a role of genetically conferred dysregulation of the (immuno)proteasome in regulating galactose-deficient IgA1 in the development of IgAN.

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Most cited references 32

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Author and article information

Journal

Journal ID (nlm-ta): Kidney Dis (Basel)

Journal ID (iso-abbrev): Kidney Dis (Basel)

Journal ID (hwp): KDD

Journal ID (publisher-id): KDD

Title: Kidney Diseases

Publisher: S. Karger AG (Basel, Switzerland )

ISSN (Print): 2296-9381

ISSN (Electronic): 2296-9357

Publication date (Electronic): 2 March 2024

Publication date Collection: June 2024

Volume: 10

Issue: 3

Pages: 167-180

Affiliations

[a ]Renal Division, Peking University First Hospital, Beijing, China

[b ]Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China

[c ]Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China

[d ]Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China

[e ]Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China

[f ]State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China

Author notes

Correspondence to: Xu-Jie Zhou, zhouxujie@ 123456bjmu.edu.cn

Lin-lin Xu, Ting Gan, and Yang Li contributed equally to this work.

Article

Publisher ID: 537987

DOI: 10.1159/000537987

PMC ID: 11149991

PubMed ID: 38835407

SO-VID: 0d2c0db5-9598-4d9f-a1c1-f6536af3f50b

License:

This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC) ( http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.

History

Date received : 12 October 2023

Date accepted : 20 February 2024

Date: 2024

Page count

Figures: 5, Tables: 2, References: 27, Pages: 14

Funding

Support was provided by National Science Foundation of China (82000680, 82022010, 82131430172, 82370709, 8197061382070733, and 82070731); Beijing Natural Science Foundation (Z190023); Academy of Medical Sciences – Newton Advanced Fellowship (NAFR13\1033); King’s College London – Peking University Health Science Center Joint Institute for Medical Research (BMU2021KCL004); Fok Ying Tung Education Foundation (171030); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2019-I2M-5-046, 2020-JKCS-009); and National High Level Hospital Clinical Research Funding (Interdisciplinary Clinical Research Project of Peking University First Hospital, 2022CR41). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.