Antonella Mulas

@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{palomba_genome-wide_2015,

title = {Genome-wide association study of susceptibility loci for breast cancer in Sardinian population},

author = {Grazia Palomba and Angela Loi and Eleonora Porcu and Antonio Cossu and Ilenia Zara and Mario Budroni and Mariano Dei and Sandra Lai and Antonella Mulas and Nina Olmeo and Maria Teresa Ionta and Francesco Atzori and Gianmauro Cuccuru and Maristella Pitzalis and Magdalena Zoledziewska and Nazario Olla and Mario Lovicu and Marina Pisano and Gon{ç}alo R Abecasis and Manuela Uda and Francesco Tanda and Kyriaki Michailidou and Douglas F Easton and Stephen J Chanock and Robert N Hoover and David J Hunter and David Schlessinger and Serena Sanna and Laura Crisponi and Giuseppe Palmieri},

doi = {10.1186/s12885-015-1392-9},

issn = {1471-2407},

year  = {2015},

date = {2015-05-01},

journal = {BMC cancer},

volume = {15},

pages = {383},

abstract = {BACKGROUND: Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. 

METHODS: We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. 

RESULTS: Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 0(-6) level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10(-5), we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16 x 10(-5)), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. 

CONCLUSIONS: This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Pistis2014,

title = {Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs},

author = {Giorgio Pistis and Eleonora Porcu and Scott I Vrieze and Carlo Sidore and Maristella Steri and Fabrice Danjou and Fabio Busonero and Antonella Mulas and Magdalena Zoledziewska and Andrea Maschio and Christine Brennan and Sandra Lai and Michael B Miller and Marco Marcelli and Maria Francesca Urru and Maristella Pitzalis and Robert H Lyons and Hyun M Kang and Chris M Jones and Andrea Angius and William G Iacono and David Schlessinger and Matt McGue and Francesco Cucca and Gon ç and Serena Sanna},

url = {https://doi.org/10.1038/ejhg.2014.216},

doi = {10.1038/ejhg.2014.216},

year  = {2014},

date = {2014-01-01},

urldate = {2014-01-01},

journal = {European Journal of Human Genetics},

volume = {23},

number = {7},

pages = {975--983},

publisher = {Springer Science and Business Media LLC},

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}

}

@article{Sanna2011,

title = {Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability},

author = {Serena Sanna and Bingshan Li and Antonella Mulas and Carlo Sidore and Hyun M Kang and Anne U Jackson and Maria Grazia Piras and Gianluca Usala and Giuseppe Maninchedda and Alessandro Sassu and Fabrizio Serra and Maria Antonietta Palmas and William H Wood and Inger Nj ø and Markku Laakso and Kristian Hveem and Jaakko Tuomilehto and Timo A Lakka and Rainer Rauramaa and Michael Boehnke and Francesco Cucca and Manuela Uda and David Schlessinger and Ramaiah Nagaraja and Gon ç},

editor = {Greg Gibson},

url = {https://doi.org/10.1371/journal.pgen.1002198},

doi = {10.1371/journal.pgen.1002198},

year  = {2011},

date = {2011-01-01},

journal = {PLoS Genetics},

volume = {7},

number = {7},

pages = {e1002198},

publisher = {Public Library of Science (PLoS)},

keywords = {},

pubstate = {published},

tppubtype = {article}

}