Magdalena Zoledziewska

@article{pmid32929287,

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

author = {V Orrù and M Steri and C Sidore and M Marongiu and V Serra and S Olla and G Sole and S Lai and M Dei and A Mulas and F Virdis and MG Piras and M Lobina and M Marongiu and M Pitzalis and F Deidda and A Loizedda and S Onano and M Zoledziewska and S Sawcer and M Devoto and M Gorospe and GR Abecasis and M Floris and M Pala and D Schlessinger and E Fiorillo and F Cucca},

year  = {2020},

date = {2020-01-01},

journal = {Nat Genet},

volume = {52},

number = {10},

pages = {1036--1045},

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 × 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{pmid31176875b,

title = {The gut microbiota perspective for interventions in MS},

author = { M. Zoledziewska},

year  = {2019},

date = {2019-01-01},

volume = {18},

number = {8},

pages = {814--824},

abstract = {The heritable genetic variation that explains phenotypic differences in a population fluctuates for different autoimmune disorders. Particularly in multiple sclerosis (MS) etiology, modest genetic and major environmental effects emerge. Increasingly recognized as a major environmentally shaped contributor to disease and treatment outcomes are gut microbiota. As discussed here, the observed impact of gut microbiome on MS pathophysiology, involves both quantitative and functional changes in composition, metabolism, gut permeability, homeostasis and modulation of the immune system. Although the first supplementary therapeutic interventions have been approached in general autoimmune disorders they are relatively cruder and a translation of knowledge from other pathologies is valuable but still required. Consequently initial therapeutic interventions with microbiota for autoimmune disorders could be correspondingly improved.},

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{danjou_genome-wide_2015,

title = {Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels},

author = {Fabrice Danjou and Magdalena Zoledziewska and Carlo Sidore and Maristella Steri and Fabio Busonero and Andrea Maschio and Antonella Mulas and Lucia Perseu and Susanna Barella and Eleonora Porcu and Giorgio Pistis and Maristella Pitzalis and Mauro Pala and Stephan Menzel and Sarah Metrustry and Timothy D Spector and Lidia Leoni and Andrea Angius and Manuela Uda and Paolo Moi and Swee Lay Thein and Renzo Galanello and Gon{ç}alo R Abecasis and David Schlessinger and Serena Sanna and Francesco Cucca},

doi = {10.1038/ng.3307},

issn = {1546-1718},

year  = {2015},

date = {2015-11-01},

journal = {Nature Genetics},

volume = {47},

number = {11},

pages = {1264--1271},

abstract = {We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{zoledziewska_height-reducing_2015,

title = {Height-reducing variants and selection for short stature in Sardinia},

author = {Magdalena Zoledziewska and Carlo Sidore and Charleston W K Chiang and Serena Sanna and Antonella Mulas and Maristella Steri and Fabio Busonero and Joseph H Marcus and Michele Marongiu and Andrea Maschio and Diego Ortega {Del Vecchyo} and Matteo Floris and Antonella Meloni and Alessandro Delitala and Maria Pina Concas and Federico Murgia and Ginevra Biino and Simona Vaccargiu and Ramaiah Nagaraja and Kirk E Lohmueller and UK10K Consortium and Nicholas J Timpson and Nicole Soranzo and Ioanna Tachmazidou and George Dedoussis and Eleftheria Zeggini and Understanding Society Scientific Group and Sergio Uzzau and Chris Jones and Robert Lyons and Andrea Angius and Gon{ç}alo R Abecasis and John Novembre and David Schlessinger and Francesco Cucca},

doi = {10.1038/ng.3403},

issn = {1546-1718},

year  = {2015},

date = {2015-11-01},

journal = {Nature Genetics},

volume = {47},

number = {11},

pages = {1352--1356},

abstract = {We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sanna2010,

title = {Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis.},

author = {Sanna, Serena and Pitzalis, Maristella and Zoledziewska, Magdalena and Zara, Ilenia and Sidore, Carlo and Murru, Raffaele and Whalen, Michael B and Busonero, Fabio and Maschio, Andrea and Costa, Gianna and Melis, Maria Cristina and Deidda, Francesca and Poddie, Fausto and Morelli, Laura and Farina, Gabriele and Li, Yun and Dei, Mariano and Lai, Sandra and Mulas, Antonella and Cuccuru, Gianmauro and Porcu, Eleonora and Liang, Liming and Zavattari, Patrizia and Moi, Loredana and Deriu, Elisa and Urru, M Francesca and Bajorek, Michele and Satta, Maria Anna and Cocco, Eleonora and Ferrigno, Paola and Sotgiu, Stefano and Pugliatti, Maura and Traccis, Sebastiano and Angius, Andrea and Melis, Maurizio and Rosati, Giulio and Abecasis, Gon{ç}alo R and Uda, Manuela and Marrosu, Maria Giovanna and Schlessinger, David and Cucca, Francesco},

url = {http://www.nature.com/doifinder/10.1038/ng.584 http://www.ncbi.nlm.nih.gov/pubmed/20453840 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3786343},

doi = {10.1038/ng.584},

issn = {1546-1718},

year  = {2010},

date = {2010-06-01},

journal = {Nature genetics},

volume = {42},

number = {6},

pages = {495--7},

abstract = {A genome-wide association scan of approximately 6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 x 10(-10)},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zoledziewska2009,

title = {Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia.},

author = {Zoledziewska, M and Costa, G and Pitzalis, M and Cocco, E and Melis, C and Moi, L and Zavattari, P and Murru, R and Lampis, R and Morelli, L and Poddie, F and Frongia, P and Pusceddu, P and Bajorek, M and Marras, A and Satta, A M and Chessa, A and Pugliatti, M and Sotgiu, S and Whalen, M B and Rosati, G and Cucca, F and Marrosu, M G},

url = {http://www.nature.com/doifinder/10.1038/gene.2008.84 http://www.ncbi.nlm.nih.gov/pubmed/18946483},

doi = {10.1038/gene.2008.84},

issn = {1476-5470},

year  = {2009},

date = {2009-01-01},

journal = {Genes and immunity},

volume = {10},

number = {1},

pages = {15--7},

abstract = {Variation within intron 19 of the CLEC16A (KIAA0350) gene region was recently found to be unequivocally associated with type 1 diabetes (T1D) in genome-wide association (GWA) studies in Northern European populations. A variant in intron 22 that is nearly independent of the intron 19 variant showed suggestive evidence of association with multiple sclerosis (MS). Here, we genotyped the rs725613 polymorphism, representative of the earlier reported associations with T1D within CLEC16A, in 1037 T1D cases, 1498 MS cases and 1706 matched controls, all from the founder, autoimmunity-prone Sardinian population. In these Sardinian samples, allele A of rs725613 is positively associated not only with T1D (odds ratio=1.15, P one-tail=5.1 x 10(-3)) but also, and with a comparable effect size, with MS (odds ratio=1.21, P one-tail 6.7 x 10(-5)). Taken together these data provide evidence of joint disease association in T1D and MS within CLEC16A and underline a shared disease pathway.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}