{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T22:08:07Z","timestamp":1764540487192,"version":"3.40.4"},"reference-count":27,"publisher":"S. Karger AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,1]],"date-time":"2024-01-01T00:00:00Z","timestamp":1704067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2024,1,1]],"date-time":"2024-01-01T00:00:00Z","timestamp":1704067200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Kidney Dis"],"published-print":{"date-parts":[[2024]]},"abstract":"<b><i>Introduction:<\/i><\/b> 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. <b><i>Methods:<\/i><\/b> We firstly analyzed the association of variants in the <i>UBE2L3<\/i> 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 <i>UBE2L3<\/i> were analyzed in peripheral blood mononuclear cells from 53 patients and 28 healthy controls. The associations between <i>UBE2L3<\/i> and the expression levels of genes involved in Gd-IgA1 production were also explored. <b><i>Results:<\/i><\/b> The rs131654 showed the most significant association signal in <i>UBE2L3<\/i> region (OR: 1.10, 95% CI: 1.04\u20131.16, <i>p<\/i> = 2.29 \u00d7 10<sup>\u22123<\/sup>), whose genotypes were also associated with the levels of Gd-IgA1 (<i>p<\/i> = 0.04). The rs131654 was observed to exert <i>cis-<\/i>eQTL effects on <i>UBE2L3<\/i> in various tissues and cell types, particularly in immune cell types in multiple databases. The <i>UBE2L3<\/i>, <i>LUBAC<\/i>, and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of <i>UBE2L3<\/i> were not only associated with higher proteinuria (<i>r<\/i> = 0.34, <i>p<\/i> = 0.01) and lower eGFR (<i>r<\/i> = \u22120.28, <i>p<\/i> = 0.04), but also positively correlated with the gene expression of <i>LUBAC<\/i> and other proteasome subunits. Additionally, mRNA expression levels of <i>UBE2L3<\/i> were also positively correlated with IL-6 and <i>RELA<\/i>, but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including <i>C1GALT1<\/i> and <i>C1GALT1C1<\/i>. <b><i>Conclusion:<\/i><\/b> In conclusion, by combined genetic association and differed expression analysis of <i>UBE2L3<\/i>, our data support a role of genetically conferred dysregulation of the (immuno)proteasome in regulating galactose-deficient IgA1 in the development of IgAN. <\/jats:p>","DOI":"10.1159\/000537987","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T22:00:30Z","timestamp":1709589630000},"page":"167-180","source":"Crossref","is-referenced-by-count":2,"title":["Combined Genetic Association and Differed Expression Analysis of <i>UBE2L3<\/i> Uncovers a Genetic Regulatory Role of (Immuno)proteasome in IgA Nephropathy"],"prefix":"10.1159","volume":"10","author":[{"given":"Lin-Lin","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Gan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su-Fang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Jun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji-Cheng","family":"Lv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu-Jie","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"127","published-online":{"date-parts":[[2024,3,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.579"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.48330"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3118"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006609"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1080\/0886022X.2019.1605295"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.01860213"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.12.024"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1821"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1038\/nature09814"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2013.133"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.512277"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1080\/0886022X.2017.1419972"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01422-x"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00913-z"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz888"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.03.056"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq340"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btab186"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-150-9-200905050-00006"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr917"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1038\/ng2142"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2205"},{"key":"ref24","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2000-y"},{"key":"ref25","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110175"},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.262438199"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016091043"}],"container-title":["Kidney Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/karger.com\/kdd\/article-pdf\/10\/3\/167\/4237337\/000537987.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/karger.com\/kdd\/article-pdf\/10\/3\/167\/4237337\/000537987.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T15:08:29Z","timestamp":1745420909000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000537987"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024]]},"references-count":27,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,6,4]]},"published-print":{"date-parts":[[2024,6,5]]}},"URL":"https:\/\/doi.org\/10.1159\/000537987","archive":["Portico"],"relation":{"is-supplemented-by":[{"id-type":"doi","id":"10.6084\/m9.figshare.25329847","asserted-by":"subject"}]},"ISSN":["2296-9381","2296-9357"],"issn-type":[{"type":"print","value":"2296-9381"},{"type":"electronic","value":"2296-9357"}],"subject":[],"published":{"date-parts":[[2024]]}}}