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Overexpression of the Cytokine BAFF and Autoimmunity Risk.


ABSTRACT: BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.).

SUBMITTER: Steri M 

PROVIDER: S-EPMC5605835 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Overexpression of the Cytokine BAFF and Autoimmunity Risk.

Steri Maristella M   Orrù Valeria V   Idda M Laura ML   Pitzalis Maristella M   Pala Mauro M   Zara Ilenia I   Sidore Carlo C   Faà Valeria V   Floris Matteo M   Deiana Manila M   Asunis Isadora I   Porcu Eleonora E   Mulas Antonella A   Piras Maria G MG   Lobina Monia M   Lai Sandra S   Marongiu Mara M   Serra Valentina V   Marongiu Michele M   Sole Gabriella G   Busonero Fabio F   Maschio Andrea A   Cusano Roberto R   Cuccuru Gianmauro G   Deidda Francesca F   Poddie Fausto F   Farina Gabriele G   Dei Mariano M   Virdis Francesca F   Olla Stefania S   Satta Maria A MA   Pani Mario M   Delitala Alessandro A   Cocco Eleonora E   Frau Jessica J   Coghe Giancarlo G   Lorefice Lorena L   Fenu Giuseppe G   Ferrigno Paola P   Ban Maria M   Barizzone Nadia N   Leone Maurizio M   Guerini Franca R FR   Piga Matteo M   Firinu Davide D   Kockum Ingrid I   Lima Bomfim Izaura I   Olsson Tomas T   Alfredsson Lars L   Suarez Ana A   Carreira Patricia E PE   Castillo-Palma Maria J MJ   Marcus Joseph H JH   Congia Mauro M   Angius Andrea A   Melis Maurizio M   Gonzalez Antonio A   Alarcón Riquelme Marta E ME   da Silva Berta M BM   Marchini Maurizio M   Danieli Maria G MG   Del Giacco Stefano S   Mathieu Alessandro A   Pani Antonello A   Montgomery Stephen B SB   Rosati Giulio G   Hillert Jan J   Sawcer Stephen S   D'Alfonso Sandra S   Todd John A JA   Novembre John J   Abecasis Gonçalo R GR   Whalen Michael B MB   Marrosu Maria G MG   Meloni Alessandra A   Sanna Serena S   Gorospe Myriam M   Schlessinger David D   Fiorillo Edoardo E   Zoledziewska Magdalena M   Cucca Francesco F  

The New England journal of medicine 20170401 17


<h4>Background</h4>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 pat  ...[more]

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