RT Journal Article
T1 Overexpression of the Cytokine BAFF and Autoimmunity Risk.
A1 Steri, Maristella
A1 Orrù, Valeria
A1 Idda, M Laura
A1 Pitzalis, Maristella
A1 Pala, Mauro
A1 Zara, Ilenia
A1 Sidore, Carlo
A1 Faà, Valeria
A1 Floris, Matteo
A1 Deiana, Manila
A1 Asunis, Isadora
A1 Porcu, Eleonora
A1 Mulas, Antonella
A1 Piras, Maria G
A1 Lobina, Monia
A1 Lai, Sandra
A1 Marongiu, Mara
A1 Serra, Valentina
A1 Marongiu, Michele
A1 Sole, Gabriella
A1 Busonero, Fabio
A1 Maschio, Andrea
A1 Cusano, Roberto
A1 Cuccuru, Gianmauro
A1 Deidda, Francesca
A1 Poddie, Fausto
A1 Farina, Gabriele
A1 Dei, Mariano
A1 Virdis, Francesca
A1 Olla, Stefania
A1 Satta, Maria A
A1 Pani, Mario
A1 Delitala, Alessandro
A1 Cocco, Eleonora
A1 Frau, Jessica
A1 Coghe, Giancarlo
A1 Lorefice, Lorena
A1 Fenu, Giuseppe
A1 Ferrigno, Paola
A1 Ban, Maria
A1 Barizzone, Nadia
A1 Leone, Maurizio
A1 Guerini, Franca R
A1 Piga, Matteo
A1 Firinu, Davide
A1 Kockum, Ingrid
A1 Lima Bomfim, Izaura
A1 Olsson, Tomas
A1 Alfredsson, Lars
A1 Suarez, Ana
A1 Carreira, Patricia E
A1 Castillo-Palma, Maria J
A1 Marcus, Joseph H
A1 Congia, Mauro
A1 Angius, Andrea
A1 Melis, Maurizio
A1 Gonzalez, Antonio
A1 Alarcón Riquelme, Marta E
A1 da Silva, Berta M
A1 Marchini, Maurizio
A1 Danieli, Maria G
A1 Del Giacco, Stefano
A1 Mathieu, Alessandro
A1 Pani, Antonello
A1 Montgomery, Stephen B
A1 Rosati, Giulio
A1 Hillert, Jan
A1 Sawcer, Stephen
A1 D'Alfonso, Sandra
A1 Todd, John A
A1 Novembre, John
A1 Abecasis, Gonçalo R
A1 Whalen, Michael B
A1 Marrosu, Maria G
A1 Meloni, Alessandra
A1 Sanna, Serena
A1 Gorospe, Myriam
A1 Schlessinger, David
A1 Fiorillo, Edoardo
A1 Zoledziewska, Magdalena
A1 Cucca, Francesco
AB Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).
YR 2017
FD 2017
LK http://hdl.handle.net/10668/11134
UL http://hdl.handle.net/10668/11134
LA en
DS RISalud
RD Apr 12, 2025