Edoardo Fiorillo

@article{pala_population-_2017,

title = {Population- and individual-specific regulatory variation in Sardinia},

author = {Mauro Pala and Zachary Zappala and Mara Marongiu and Xin Li and Joe R Davis and Roberto Cusano and Francesca Crobu and Kimberly R Kukurba and Michael J Gloudemans and Frederic Reinier and Riccardo Berutti and Maria G Piras and Antonella Mulas and Magdalena Zoledziewska and Michele Marongiu and Elena P Sorokin and Gaelen T Hess and Kevin S Smith and Fabio Busonero and Andrea Maschio and Maristella Steri and Carlo Sidore and Serena Sanna and Edoardo Fiorillo and Michael C Bassik and Stephen J Sawcer and Alexis Battle and John Novembre and Chris Jones and Andrea Angius and Gon{ç}alo R Abecasis and David Schlessinger and Francesco Cucca and Stephen B Montgomery},

doi = {10.1038/ng.3840},

issn = {1546-1718},

year  = {2017},

date = {2017-05-01},

journal = {Nature Genetics},

volume = {49},

number = {5},

pages = {700--707},

abstract = {Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{steri_overexpression_2017,

title = {Overexpression of the Cytokine BAFF and Autoimmunity Risk},

author = {Maristella Steri and Valeria Orrù and Laura M Idda and Maristella Pitzalis and Mauro Pala and Ilenia Zara and Carlo Sidore and Valeria Faà 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 {Alarc{ó}n Riquelme} and Berta M da 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 D'Alfonso and John A Todd and John Novembre and Gon{ç}alo 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},

issn = {1533-4406},

year  = {2017},

date = {2017-01-01},

journal = {The New England Journal of Medicine},

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→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.).},

note = {See Editorials, Korn T, Oukka M. A BAFFling Association between Malaria Resistance and the Risk of Multiple Sclerosis. N Engl J Med. 2017 Apr 27;376(17):1680-1681. doi: 10.1056/NEJMe1700720.; Stohl W., Systemic lupus erythematosus: BAFF emerges from the genetic shadows. Nat Rev Rheumatol. 2017 Jun 15. doi: 10.1038/nrrheum.2017.99; Comabella M. Neuroimmunology: B cells and variant BAFF in autoimmune disease. Nat Rev Neurol. 2017 Jun 16. doi: 10.1038/nrneurol.2017.87.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{de_vries_meta-analysis_2016,

title = {A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration},

author = {Paul S de Vries and Daniel I Chasman and Maria Sabater-Lleal and Ming-Huei Chen and Jennifer E Huffman and Maristella Steri and Weihong Tang and Alexander Teumer and Riccardo E Marioni and Vera Grossmann and Jouke J Hottenga and Stella Trompet and Martina M{ü}ller-Nurasyid and Jing Hua Zhao and Jennifer A Brody and Marcus E Kleber and Xiuqing Guo and Jie Jin Wang and Paul L Auer and John R Attia and Lisa R Yanek and Tarunveer S Ahluwalia and Jari Lahti and Cristina Venturini and Toshiko Tanaka and Lawrence F Bielak and Peter K Joshi and Ares Rocanin-Arjo and Ivana Kolcic and Pau Navarro and Lynda M Rose and Christopher Oldmeadow and Helene Riess and Johanna Mazur and Saonli Basu and Anuj Goel and Qiong Yang and Mohsen Ghanbari and Gonneke Willemsen and Ann Rumley and Edoardo Fiorillo and Anton J M de Craen and Anne Grotevendt and Robert Scott and Kent D Taylor and Graciela E Delgado and Jie Yao and Annette Kifley and Charles Kooperberg and Rehan Qayyum and Lorna M Lopez and Tina L Berentzen and Katri R{ä}ikk{ö}nen and Massimo Mangino and Stefania Bandinelli and Patricia A Peyser and Sarah Wild and David-Alexandre Tr{é}gou{ë}t and Alan F Wright and Jonathan Marten and Tatijana Zemunik and Alanna C Morrison and Bengt Sennblad and Geoffrey Tofler and Moniek P M de Maat and Eco J C de Geus and Gordon D Lowe and Magdalena Zoledziewska and Naveed Sattar and Harald Binder and Uwe V{ö}lker and Melanie Waldenberger and Kay-Tee Khaw and Barbara Mcknight and Jie Huang and Nancy S Jenny and Elizabeth G Holliday and Lihong Qi and Mark G Mcevoy and Diane M Becker and John M Starr and Antti-Pekka Sarin and Pirro G Hysi and Dena G Hernandez and Min A Jhun and Harry Campbell and Anders Hamsten and Fernando Rivadeneira and Wendy L Mcardle and Eline P Slagboom and Tanja Zeller and Wolfgang Koenig and Bruce M Psaty and Talin Haritunians and Jingmin Liu and Aarno Palotie and Andr{é} G Uitterlinden and David J Stott and Albert Hofman and Oscar H Franco and Ozren Polasek and Igor Rudan and Pierre-Emmanuel Morange and James F Wilson and Sharon L R Kardia and Luigi Ferrucci and Tim D Spector and Johan G Eriksson and Torben Hansen and Ian J Deary and Lewis C Becker and Rodney J Scott and Paul Mitchell and Winfried M{ä}rz and Nick J Wareham and Annette Peters and Andreas Greinacher and Philipp S Wild and Wouter J Jukema and Dorret I Boomsma and Caroline Hayward and Francesco Cucca and Russell Tracy and Hugh Watkins and Alex P Reiner and Aaron R Folsom and Paul M Ridker and Christopher J O'Donnell and Nicholas L Smith and David P Strachan and Abbas Dehghan},

doi = {10.1093/hmg/ddv454},

issn = {1460-2083},

year  = {2016},

date = {2016-01-01},

journal = {Human Molecular Genetics},

volume = {25},

number = {2},

pages = {358--370},

abstract = {Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{wu_autoimmunity-associated_2014,

title = {Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive Ŧ cells},

author = {Dennis J Wu and Wenbo Zhou and Sarah Enouz and Valeria Orr{ú} and Stephanie M Stanford and Christian J Maine and Novella Rapini and Kristy Sawatzke and Isaac Engel and Edoardo Fiorillo and Linda A Sherman and Mitch Kronenberg and Dietmar Zehn and Erik Peterson and Nunzio Bottini},

doi = {10.1371/journal.pone.0086677},

issn = {1932-6203},

year  = {2014},

date = {2014-01-01},

journal = {PloS One},

volume = {9},

number = {2},

pages = {e86677},

abstract = {A C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for human autoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays a role in thymic selection. However, the mechanism of action of the R620W variant in autoimmunity remains unclear. One model holds that LYP-W620 is a gain-of-function phosphatase that causes alterations in thymic negative selection and/or thymic output of regulatory T cells (Treg) through inhibition of thymic TCR signaling. To test this model, we generated mice in which the human LYP-W620 variant or its phosphatase-inactive mutant are expressed in developing thymocytes under control of the proximal Lck promoter. We found that LYP-W620 expression results in diminished thymocyte TCR signaling, thus modeling a "gain-of-function" of LYP at the signaling level. However, LYP-W620 transgenic mice display no alterations of thymic negative selection and no anomalies in thymic output of CD4(+)Foxp3(+) Treg were detected in these mice. Lck promoter-directed expression of the human transgene also causes no alteration in thymic repertoire or increase in disease severity in a model of rheumatoid arthritis, which depends on skewed thymic selection of CD4(+) T cells. Our data suggest that a gain-of-function of LYP is unlikely to increase risk of autoimmunity through alterations of thymic selection and that LYP likely acts in the periphery perhaps selectively in regulatory T cells or in another cell type to increase risk of autoimmunity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{orru_genetic_2013,

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

author = {Valeria Orrù 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 Gon{ç}alo R Abecasis and Edoardo Fiorillo and Serena Sanna and Francesco Cucca},

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

issn = {1097-4172},

year  = {2013},

date = {2013-09-01},

journal = {Cell},

volume = {155},

number = {1},

pages = {242--56},

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}

}