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Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case\u2013control study includes a cohort (women, 18\u201360\u00a0years old) of 100 patients (48% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of \u0394BAFF, \u03b2APRIL, and \u03b5APRIL, and next-generation sequencing to genotype the cytokine (<jats:italic>TNFSF13<\/jats:italic> and <jats:italic>TNFSF13B<\/jats:italic>) and receptor (<jats:italic>TNFRSF13B<\/jats:italic>, <jats:italic>TNFRSF17<\/jats:italic> and <jats:italic>TNFRSF13C<\/jats:italic>) genes. The statistical tests used were: Kruskal\u2013Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p\u2009\u2264\u20090.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (r<jats:sub>s<\/jats:sub>\u2009=\u20090.67, p\u2009\u2264\u20090.001) and \u03b2APRIL levels were lower in patients with nephritis (p\u2009=\u20090.04), and \u0394BAFF levels were lower in patients with dsDNA antibodies (p\u2009=\u20090.04). Rare variants of <jats:italic>TNFSF13 <\/jats:italic>and<jats:italic> TNFRSF13B <\/jats:italic>and<jats:italic> TNFSF13<\/jats:italic> p.Gly67Arg and <jats:italic>TNFRSF13B<\/jats:italic> p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF\/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.<\/jats:p>","DOI":"10.1038\/s41598-022-15549-0","type":"journal-article","created":{"date-parts":[[2022,7,2]],"date-time":"2022-07-02T11:02:44Z","timestamp":1656759764000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus"],"prefix":"10.1038","volume":"12","author":[{"given":"Pilar","family":"Ortiz-Aljaro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco Antonio","family":"Montes-Cano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9-Ra\u00fal","family":"Garc\u00eda-Lozano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Aquino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Carmona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Perez-Florido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Jos\u00e9","family":"Garc\u00eda-Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn","family":"Dopazo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Francisca","family":"Gonz\u00e1lez-Escribano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,2]]},"reference":[{"key":"15549_CR1","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1080\/1744666X.2017.1327352","volume":"13","author":"GJ Pons-Estel","year":"2017","unstructured":"Pons-Estel, G. 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