{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:18:36Z","timestamp":1785403116498,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82000422"],"award-info":[{"award-number":["82000422"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82000422"],"award-info":[{"award-number":["82000422"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Hunan Provincial Natural Science Foundation of China","doi-asserted-by":"crossref","award":["2025JJ70444"],"award-info":[{"award-number":["2025JJ70444"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Autophagy plays a role in systemic lupus erythematosus (SLE) pathogenesis. Nevertheless, the specific genetic determinants underpinning this process remain poorly characterized. Summary data-based Mendelian randomization (SMR) analysis was therefore utilized to pinpoint autophagy-related genes associated with SLE risk. Methods: We analyzed 700 autophagy-related genes, integrating methylation quantitative trait loci (mQTL), expression QTL (eQTL) from blood and relevant tissue, and protein QTL (pQTL) data with genome-wide association studies (GWAS) data on SLE from the IEU dataset (discovery). GWAS data from FinnGen and the GWAS Catalog were used as replication datasets. Colocalization analysis identified shared genetic variants. Blood samples from 10 healthy control and 20 SLE patients were collected and analyzed for the expression of candidate genes. Results: Our SMR analysis identified suggestive associations between NLRP6 expression (OR = 0.528, 95%CI = 0.291\u20130.96) and p27Kip1 protein abundance (OR = 0.269, 95%CI = 0.08\u20130.904) with SLE susceptibility in the discovery cohort, supported by colocalization evidence. Additionally, we found that the methylation of the NLRP6 promoter (cg06432119) was significantly increased, while NLRP6 expression and p27Kip1 level were significantly decreased in SLE patients compared to controls. Furthermore, NLRP6 mRNA expression was significantly negatively correlated with the SLE severity (SLEDAI-2000). Conclusions: These findings not only prioritized candidate genes via SMR analysis but also provided evidence of epigenetic dysregulation of NLRP6 and its correlation with disease activity in SLE, thereby offering novel insights into the underlying mechanisms.<\/jats:p>","DOI":"10.3390\/genes17040466","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T07:37:19Z","timestamp":1776325039000},"page":"466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-Omics Mendelian Randomization and Clinical Validation Implicate NLRP6 as a Candidate Autophagy-Related Gene in Systemic Lupus Erythematosus"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2808-650X","authenticated-orcid":false,"given":"Daan","family":"Nie","sequence":"first","affiliation":[{"name":"Department of Cardiology, Hunan University of Medicine General Hospital, Huaihua 418000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hunan University of Medicine General Hospital, Huaihua 418000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kecheng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yikai","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4035-4666","authenticated-orcid":false,"given":"Shengyan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4180-3434","authenticated-orcid":false,"given":"Zhipeng","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.molmed.2017.05.006","article-title":"Pathogenesis of human systemic lupus erythematosus: A cellular perspective","volume":"23","author":"Moulton","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.4236\/ojra.2021.114014","article-title":"A review of systemic lupus erythematosus (SLE): Symptoms, risk factors, treatment, and health related quality of life issues","volume":"11","year":"2021","journal-title":"Open J. Rheumatol. Autoimmune Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1177\/0961203319888691","article-title":"Prevalence and incidence of systemic lupus erythematosus and associated outcomes in the 2009\u20132016 US Medicare population","volume":"29","author":"Li","year":"2020","journal-title":"Lupus"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/s41584-021-00668-1","article-title":"Global epidemiology of systemic lupus erythematosus","volume":"17","author":"Barber","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ejim.2023.02.004","article-title":"Mortality and causes of death in systemic lupus erythematosus over the last decade: Data from a large population-based study","volume":"112","author":"Zen","year":"2023","journal-title":"Eur. J. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.rdc.2021.04.012","article-title":"Treatment update in systemic lupus erythematous","volume":"47","author":"Hoi","year":"2021","journal-title":"Rheum. Dis. Clin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"91","DOI":"10.33084\/bjop.v4i2.1950","article-title":"Systemic Lupus Erythematosus Disease: An Overview of the Clinical Approach to Pathogenesis, Diagnosis, and Treatment","volume":"4","author":"Nimesh","year":"2021","journal-title":"Borneo J. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/s00109-015-1297-8","article-title":"Autophagy in autoimmune disease","volume":"93","author":"Yang","year":"2015","journal-title":"J. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1177\/0961203318776108","article-title":"Evaluation of ATG5 polymorphisms in Italian patients with systemic lupus erythematosus: Contribution to disease susceptibility and clinical phenotypes","volume":"27","author":"Ciccacci","year":"2018","journal-title":"Lupus"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.trsl.2022.03.004","article-title":"Cell type-specific mechanistic target of rapamycin-dependent distortion of autophagy pathways in lupus nephritis","volume":"245","author":"Caza","year":"2022","journal-title":"Transl. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Colasanti, T., Spinelli, F.R., Barbati, C., Ceccarelli, F., Scarpa, S., Vomero, M., Alessandri, C., Valesini, G., and Conti, F. (2022). Belimumab decreases autophagy and citrullination in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Cells, 11.","DOI":"10.3390\/cells11020262"},{"key":"ref_12","first-page":"A54","article-title":"P17 Autophagy-based unconventional secretion of B cell activating factor (BAFF) by monocytes in Systemic Lupus Erythematosus (SLE)","volume":"11","author":"Nikoleri","year":"2024","journal-title":"Lupus Sci. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103132","DOI":"10.1016\/j.autrev.2022.103132","article-title":"Autophagy in lupus nephritis: A delicate balance between regulation and disease","volume":"21","author":"Faravelli","year":"2022","journal-title":"Autoimmun. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/s41398-021-01348-0","article-title":"Mendelian randomization integrating GWAS and eQTL data revealed genes pleiotropically associated with major depressive disorder","volume":"11","author":"Yang","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Liu, X., Miao, Y., Liu, C., Lu, W., Feng, Q., and Zhang, Q. (2023). Identification of multiple novel susceptibility genes associated with autoimmune thyroid disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1161311"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1038\/s41467-018-03371-0","article-title":"Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits","volume":"9","author":"Wu","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1038\/s41588-021-00913-z","article-title":"Large-scale cis-and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression","volume":"53","author":"Claringbould","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1038\/s41588-021-00978-w","article-title":"Large-scale integration of the plasma proteome with genetics and disease","volume":"53","author":"Ferkingstad","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Giambartolomei, C., Vukcevic, D., Schadt, E.E., Franke, L., Hingorani, A.D., Wallace, C., and Plagnol, V. (2014). Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet, 10.","DOI":"10.1371\/journal.pgen.1004383"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e627","DOI":"10.1002\/cpz1.627","article-title":"Bayesian Genetic Colocalization Test of Two Traits Using coloc","volume":"2","author":"Rasooly","year":"2022","journal-title":"Curr. Protoc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/s41586-023-06034-3","article-title":"GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19","volume":"617","author":"Rawlik","year":"2023","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chen, E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R., and Ma\u2019ayan, A. (2013). Enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-128"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e90","DOI":"10.1002\/cpz1.90","article-title":"Gene Set Knowledge Discovery with Enrichr","volume":"1","author":"Xie","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1093\/bioinformatics\/btv313","article-title":"DSigDB: Drug signatures database for gene set analysis","volume":"31","author":"Yoo","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3899\/jrheum.220089","article-title":"Cutaneous Involvement in Systemic Lupus Erythematosus: A Review for the Rheumatologist","volume":"50","author":"Stull","year":"2023","journal-title":"J. Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1824624","DOI":"10.1155\/2019\/1824624","article-title":"The Role of Toll-Like Receptors in Skin Host Defense, Psoriasis, and Atopic Dermatitis","volume":"2019","author":"Sun","year":"2019","journal-title":"J. Immunol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1042\/BCJ20160005","article-title":"Mechanisms of Hsp90 regulation","volume":"473","author":"Prodromou","year":"2016","journal-title":"Biochem. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.jid.2021.04.014","article-title":"Neutrophils as Drivers of Immune Dysregulation in Autoimmune Diseases with Skin Manifestations","volume":"142","author":"Nakabo","year":"2022","journal-title":"J. Invest. Dermatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/imm.13293","article-title":"The NLRP6 inflammasome","volume":"162","author":"Zheng","year":"2021","journal-title":"Immunology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1007\/s00109-020-01962-3","article-title":"NLRP6 contributes to inflammation and brain injury following intracerebral haemorrhage by activating autophagy","volume":"98","author":"Xiao","year":"2020","journal-title":"J. Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"111454","DOI":"10.1016\/j.celrep.2022.111454","article-title":"Estrogen receptor \u03b2 activation inhibits colitis by promoting NLRP6-mediated autophagy","volume":"41","author":"Fan","year":"2022","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Yi, Y.-S. (2021). Functional interplay between methyltransferases and inflammasomes in inflammatory responses and diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147580"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/s41385-020-0256-z","article-title":"The NLRP6 inflammasome in health and disease","volume":"13","author":"Ghimire","year":"2020","journal-title":"Mucosal Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.cell.2014.01.026","article-title":"NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion","volume":"156","author":"Wlodarska","year":"2014","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1002\/eji.201847679","article-title":"Autophagy and immunological aberrations in systemic lupus erythematosus","volume":"49","author":"Qi","year":"2019","journal-title":"Eur. J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.semarthrit.2019.09.022","article-title":"Advances in systemic lupus erythematosus pathogenesis via mTOR signaling pathway","volume":"50","author":"He","year":"2020","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ajhg.2012.11.018","article-title":"Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians","volume":"92","author":"Yang","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Cristofani, R., Piccolella, M., Crippa, V., Tedesco, B., Montagnani Marelli, M., Poletti, A., and Moretti, R.M. (2021). The role of HSPB8, a component of the chaperone-assisted selective autophagy machinery, in cancer. Cells, 10.","DOI":"10.3390\/cells10020335"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7021","DOI":"10.4049\/jimmunol.176.11.7021","article-title":"Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis","volume":"176","author":"Roelofs","year":"2006","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s40478-015-0267-2","article-title":"Small heat shock proteins are induced during multiple sclerosis lesion development in white but not grey matter","volume":"3","author":"Peferoen","year":"2015","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1080\/15548627.2021.1953262","article-title":"A Dictyostelium model for BPAN disease reveals a functional relationship between the WDR45\/WIPI4 homolog Wdr45L and Vmp1 in the regulation of autophagy-associated PtdIns3P and ER stress","volume":"18","author":"Vincent","year":"2022","journal-title":"Autophagy"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/466\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T04:17:19Z","timestamp":1776485839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/466"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["genes17040466"],"URL":"https:\/\/doi.org\/10.3390\/genes17040466","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]}}}