Valeria Orrù

@article{Orru2020-uk,

title = {Complex genetic signatures in immune cells underlie autoimmunity  and inform therapy},

author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},

doi = {10.1038/s41588-020-0684-4},

year  = {2020},

date = {2020-10-01},

urldate = {2020-10-01},

journal = {Nat. Genet.},

volume = {52},

number = {10},

pages = {1036--1045},

publisher = {Springer Science and Business Media LLC},

abstract = {We report on the influence of ~22 million variants on 731 immune 

 cell traits in a cohort of 3,757 Sardinians. We detected 122 

 significant (P < 1.28 $times$ 10-11) independent association 

 signals for 459 cell traits at 70 loci (53 of them novel) 

 identifying several molecules and mechanisms involved in cell 

 regulation. Furthermore, 53 signals at 36 loci overlapped with 

 previously reported disease-associated signals, predominantly 

 for autoimmune disorders, highlighting intermediate phenotypes 

 in pathogenesis. Collectively, our findings illustrate complex 

 genetic regulation of immune cells with highly selective effects 

 on autoimmune disease risk at the cell-subtype level. These 

 results identify drug-targetable pathways informing the design 

 of more specific treatments for autoimmune diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Steri2017-ix,

title = {Överexpression of the cytokine BAFF and autoimmunity risk},

author = {Maristella Steri and Valeria Orr`u and M Laura Idda and Maristella Pitzalis and Mauro Pala and Ilenia Zara and Carlo Sidore and Valeria Fa`a and Matteo Floris and Manila Deiana and Isadora Asunis and Eleonora Porcu and Antonella Mulas and Maria G Piras and Monia Lobina and Sandra Lai and Mara Marongiu and Valentina Serra and Michele Marongiu and Gabriella Sole and Fabio Busonero and Andrea Maschio and Roberto Cusano and Gianmauro Cuccuru and Francesca Deidda and Fausto Poddie and Gabriele Farina and Mariano Dei and Francesca Virdis and Stefania Olla and Maria A Satta and Mario Pani and Alessandro Delitala and Eleonora Cocco and Jessica Frau and Giancarlo Coghe and Lorena Lorefice and Giuseppe Fenu and Paola Ferrigno and Maria Ban and Nadia Barizzone and Maurizio Leone and Franca R Guerini and Matteo Piga and Davide Firinu and Ingrid Kockum and Izaura Lima Bomfim and Tomas Olsson and Lars Alfredsson and Ana Suarez and Patricia E Carreira and Maria J Castillo-Palma and Joseph H Marcus and Mauro Congia and Andrea Angius and Maurizio Melis and Antonio Gonzalez and Marta E Alarcón Riquelme and Berta M Silva and Maurizio Marchini and Maria G Danieli and Stefano Del Giacco and Alessandro Mathieu and Antonello Pani and Stephen B Montgomery and Giulio Rosati and Jan Hillert and Stephen Sawcer and Sandra DÁlfonso and John A Todd and John Novembre and Gonc calo R Abecasis and Michael B Whalen and Maria G Marrosu and Alessandra Meloni and Serena Sanna and Myriam Gorospe and David Schlessinger and Edoardo Fiorillo and Magdalena Zoledziewska and Francesco Cucca},

doi = { 10.1056/NEJMoa1610528},

year  = {2017},

date = {2017-04-01},

urldate = {2017-04-01},

journal = {N. Engl. J. Med.},

volume = {376},

number = {17},

pages = {1615--1626},

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$rightarrow$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.).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Orru2013-pb,

title = {Genetic variants regulating immune cell levels in health and  disease},

author = {Valeria Örr`u and Maristella Steri and Gabriella Sole and Carlo Sidore and Francesca Virdis and Mariano Dei and Sandra Lai and Magdalena Zoledziewska and Fabio Busonero and Antonella Mulas and Matteo Floris and Wieslawa I Mentzen and Silvana A M Urru and Stefania Olla and Michele Marongiu and Maria G Piras and Monia Lobina and Andrea Maschio and Maristella Pitzalis and Maria F Urru and Marco Marcelli and Roberto Cusano and Francesca Deidda and Valentina Serra and Manuela Oppo and Rosella Pilu and Frederic Reinier and Riccardo Berutti and Luca Pireddu and Ilenia Zara and Eleonora Porcu and Alan Kwong and Christine Brennan and Brendan Tarrier and Robert Lyons and Hyun M Kang and Sergio Uzzau and Rossano Atzeni and Maria Valentini and Davide Firinu and Lidia Leoni and Gianluca Rotta and Silvia Naitza and Andrea Angius and Mauro Congia and Michael B Whalen and Chris M Jones and David Schlessinger and Gonc calo R Abecasis and Edoardo Fiorillo and Serena Sanna and Francesco" Cucca},

doi = {10.1016/j.cell.2013.08.041},

year  = {2013},

date = {2013-09-01},

urldate = {2013-09-01},

journal = {Cell},

volume = {155},

number = {1},

pages = {242--256},

abstract = {The complex network of specialized cells and molecules in the 

 immune system has evolved to defend against pathogens, but 

 inadvertent immune system attacks on ``self'' result in 

 autoimmune disease. Both genetic regulation of immune cell levels 

 and their relationships with autoimmunity are largely 

 undetermined. Here, we report genetic contributions to 

 quantitative levels of 95 cell types encompassing 272 immune 

 traits, in a cohort of 1,629 individuals from four clustered 

 Sardinian villages. We first estimated trait heritability, 

 showing that it can be substantial, accounting for up to 87% of 

 the variance (mean 41%). Next, by assessing ∼8.2 million 

 variants that we identified and confirmed in an extended set of 

 2,870 individuals, 23 independent variants at 13 loci associated 

 with at least one trait. Notably, variants at three loci (HLA, 

 IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease 

 associations. These results connect specific cellular phenotypes 

 to specific genetic variants, helping to explicate their 

 involvement in disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zoledziewska2008-oq,

title = {Further evidence of a primary, causal association of the  PTPN22 620W variant with type 1 diabetes},

author = {Magdalena Zoledziewska and Chiara Perra and Valeria Orr`u and Loredana Moi and Paola Frongia and Mauro Congia and Nunzio Bottini and Francesco Cucca},

doi = {10.2337/db07-0289},

year  = {2008},

date = {2008-01-01},

urldate = {2008-01-01},

journal = {Diabetes},

volume = {57},

number = {1},

pages = {229--234},

publisher = {Ämerican Diabetes Association},

abstract = {ÖBJECTIVE: The minor allele of the nonsynonymous single 

 nucleotide polymorphism (SNP) +1858C>T within the PTPN22 gene is 

 positively associated with type 1 diabetes and other autoimmune 

 diseases. Genetic and functional data underline its causal 

 effect, but some studies suggest that this polymorphism does not 

 entirely explain disease association of the PTPN22 region. The 

 aim of this study was to evaluate type 1 diabetes association 

 within this gene in the Sardinian population. RESEARCH DESIGN 

 AND METHODS: We resequenced the exons and potentially relevant 

 portions of PTPN22 and detected 24 polymorphisms (23 SNPs and 1 

 deletion insertion polymorphism [DIP]), 8 of which were novel. A 

 representative set of 14 SNPs and the DIP were sequentially 

 genotyped and assessed for disease association in 794 families, 

 490 sporadic patients, and 721 matched control subjects. 

 RESULTS: The +1858C>T variant, albeit rare in the general 

 Sardinian population (allele frequency 0.014), was positively associated with type 1 diabetes (P(one tail) = 3.7 x 10(-3)). In 

 contrast, the background haplotype in which this mutation 

 occurred was common (haplotype frequency 0.117) and neutrally 

 associated with disease. We did not confirm disease associations 

 reported in other populations for non +1858C>T variants 

 (rs2488457, rs1310182, and rs3811021), although they were 

 present in appreciable frequencies in Sardinia. Additional weak 

 disease associations with rare variants were detected in the 

 Sardinian families but not confirmed in independent case-control 

 sample sets and are most likely spurious. CONCLUSIONS: We 

 provide further evidence that the +1858C>T polymorphism is 

 primarily associated with type 1 diabetes and exclude major 

 contributions from other purportedly relevant variants within 

 this gene."},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Vang2005-xl,

title = {Äutoimmune-associated lymphoid tyrosine phosphatase is a  gain-of-function variant},

author = {Torkel Vang and Mauro Congia and Maria Doloretta Macis and Lucia Musumeci and Valeria Orr'u and Patrizia Zavattari and Konstantina Nika and Lutz Tautz and Kjetil Taskén and Francesco Cucca and Tomas Mustelin and Nunzio Bottini},

doi = {10.1038/ng1673},

year  = {2005},

date = {2005-12-01},

urldate = {2005-12-01},

journal = {Nat. Genet.},

volume = {37},

number = {12},

pages = {1317--1319},

publisher = {Springer Science and Business Media LLC},

abstract = {Ä SNP in the gene PTPN22 is associated with type 1 diabetes, 

 rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease 

 and other autoimmune disorders. T cells from carriers of the 

 predisposing allele produce less interleukin-2 upon TCR 

 stimulation, and the encoded phosphatase has higher catalytic 

 activity and is a more potent negative regulator of T lymphocyte 

 activation. We conclude that the autoimmune-predisposing allele 

 is a gain-of-function mutant."},

keywords = {},

pubstate = {published},

tppubtype = {article}

}