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Genome\u2010wide association studies have identified several systemic lupus erythematosus (SLE) risk single\u2010nucleotide polymorphisms (SNPs) enriched in the <jats:italic>IRF5<\/jats:italic> locus. However, no comprehensive genome editing\u2013based functional analysis exists to establish a direct link between these variants and altered <jats:italic>IRF5<\/jats:italic> expression, particularly for enhancer variants. This study was undertaken to dissect the regulatory function and mechanisms of SLE <jats:italic>IRF5<\/jats:italic> enhancer risk variants and to explore the utilization of clustered regularly interspaced short palindromic repeat interference (CRISPRi) to regulate the expression of disease risk gene to intervene in the disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Epigenomic profiles and expression quantitative trait locus analysis were applied to prioritize putative functional variants in the <jats:italic>IRF5<\/jats:italic> locus. CRISPR\u2010mediated deletion, activation, and interference were performed to investigate the genetic function of rs4728142. Allele\u2010specific chromatin immunoprecipitation\u2013quantitative polymerase chain reaction and allele\u2010specific formaldehyde\u2010assisted isolation of regulatory element\u2013quantitative polymerase chain reaction were used to decipher the mechanism of alleles differentially regulating <jats:italic>IRF5<\/jats:italic> expression. The CRISPRi approach was used to evaluate the intervention effect in monocytes from SLE patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SLE risk SNP rs4728142 was located in an enhancer region, indicating a disease\u2010related regulatory function, and risk allele rs4728142\u2010A was closely associated with increased <jats:italic>IRF5<\/jats:italic> expression. We demonstrated that an rs4728142\u2010containing region could act as an enhancer to regulate the expression of <jats:italic>IRF5<\/jats:italic>. Moreover, rs4728142 affected the binding affinity of zinc finger and BTB domain\u2013containing protein 3 (ZBTB3), a transcription factor involved in regulation. Furthermore, in monocytes from SLE patients, CRISPR\u2010based interference with the regulation of this enhancer attenuated the production of disease\u2010associated cytokines.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results demonstrate that the rs4728142\u2010A allele increases the SLE risk by affecting ZBTB3 binding, chromatin status, and regulating <jats:italic>IRF5<\/jats:italic> expression, establishing a biologic link between genetic variation and lupus pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42390","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T03:22:42Z","timestamp":1665976962000},"page":"574-585","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Integrative Functional Genomics Identifies Systemic Lupus Erythematosus Causal Genetic Variant in the <scp><i>IRF5<\/i><\/scp> Risk Locus"],"prefix":"10.1002","volume":"75","author":[{"given":"Guojun","family":"Hou","sequence":"first","affiliation":[{"name":"Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China, and State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Xu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai 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