@article{pmid7795648,

title = {X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene},

author = {A Villa and L Notarangelo and P Macchi and E Mantuano and G Cavagni and D Brugnoni and D Strina and M C Patrosso and U Ramenghi and M G Sacco},

year  = {1995},

date = {1995-01-01},

journal = {Nat Genet},

volume = {9},

number = {4},

pages = {414--417},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cucca_insulin-dependent_1994,

title = {Insulin-dependent diabetes mellitus and the major histocompatibility complex peptide transporters TAP1 and TAP2: no association in a population with a high disease incidence.},

author = {Cucca, F. and Congia, M. and Trowsdale, J. and Powis, S. H.},

issn = {0001-2815 0001-2815},

year  = {1994},

date = {1994-10-01},

journal = {Tissue Antigens},

volume = {44},

number = {4},

pages = {234--240},

abstract = {Although many studies have established an association between insulin-dependent diabetes mellitus (IDDM) and the class II region of the human major histocompatibility complex (MHC), it has been difficult to assign susceptibility to a single locus. Recently, two antigen-processing genes, TAP1 and TAP2, have been identified within the region. Previous studies have reached conflicting conclusions as to the role of these genes in IDDM; it is uncertain whether an increased frequency of the allele TAP2A and a concomitant decrease in TAP2B are independent disease associations or secondary to linkage disequilibrium (LD) between TAP2A and HLA-DR3. To further investigate this question, we have characterized TAP1 and TAP2 alleles in 129 IDDM patients from Sardinia, a population with limited genetic heterogeneity and a high disease incidence. When compared to 90 random controls, the only significant difference was a decrease in the minor allele TAP2C in patients. However, when HLA-DR and -DQ matched controls were compared, this difference disappeared. Further analysis suggested that TAP2C was in LD with HLA-DRB1*1401 and subtypes of HLA-DRB1*11, alleles which were not observed in the IDDM population. LD was also observed between other TAP and},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid7833930,

title = {Mutations in the vasopressin V2-receptor gene in three families of Italian descent with nephrogenic diabetes insipidus},

author = { V. Faà and M. L. Ventruto and S. Loche and M. Bozzola and R. Podda and A. Cao and M. C. Rosatelli},

year  = {1994},

date = {1994-09-01},

journal = {Hum Mol Genet},

volume = {3},

number = {9},

pages = {1685--1686},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cucca_hla-dqb1*0305_1994,

title = {HLA-DQB1*0305 and -DQB1*0304 alleles among Sardinians. Evolutionary and practical implications for oligotyping.},

author = {Cucca, F. and Frau, F. and Lampis, R. and Floris, M. and Argiolas, L. and Macis, D. and Cao, A. and De Virgiliis, S. and Congia, M.},

issn = {0198-8859 0198-8859},

year  = {1994},

date = {1994-06-01},

journal = {Hum Immunol},

volume = {40},

number = {2},

pages = {143--149},

abstract = {This study, performed in individuals of Sardinian descent, reports an epidemiologic and molecular analysis of the recently identified DQB1*0304 and DQB1*0305 alleles. These two alleles having a gene frequency of 0.017 and 0.005, respectively, are not uncommon in Sardinia and are distributed fairly uniformly on the island. The analysis of DQB1 second and third exons of the two alleles revealed that although they have always been found included within the same DRB1*0403-DQA1*03 haplotype, they had a different origin. The sequence pattern of DQB1*0305 confirmed that it originated from the DQB1*0302 "recipient" gene by the insertion of a DQB1*0402 nucleotide stretch, within its beta-sheet region, while that of DQB1*0304 suggested that it originated from the DQB1*0301 gene, either by a single point mutation at codon 57 (GCC instead of GAC) or, alternatively, by a segmental transfer of a DQB1*0302 motif, including codon 57, within its alpha-helic region. Independently from the mechanism of generation, the fact that DQB1*0304 originated from DQB1*0301 allele was intriguing considering that, in over 1500 HLA class II Sardinian haplotypes examined, neither the putative parental DRB1*0403-DQA1*03-DQB1*0301 haplotypes were found. Finally, since the assignment of DQB1*0305 may be inaccurate with the traditional panel of probes commonly used for DQB1 oligotyping, the use of an additional oligonucleotide probe is recommended.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{congia_gene_1994,

title = {A gene dosage effect of the DQA1*0501/DQB1*0201 allelic combination influences the clinical heterogeneity of celiac disease.},

author = {Congia, M. and Cucca, F. and Frau, F. and Lampis, R. and Melis, L. and Clemente, M. G. and Cao, A. and De Virgiliis, S.},

issn = {0198-8859 0198-8859},

year  = {1994},

date = {1994-06-01},

journal = {Hum Immunol},

volume = {40},

number = {2},

pages = {138--142},

abstract = {This study reports the HLA-DR and DQ molecular characterization of 62 CD patients of Sardinian descent. Patients were divided in two groups (36 in group I and 26 in group II) according to the clinical features at the disease onset. Among the patients of group I, having the fully expressed form of CD and a mean age of 3 years at disease onset, a significant increase of DRB1*0301, DQA1*0501, DQB1*0201 homozygotes, encoding in cis two DQ (alpha 1*0501, beta 1*0201) susceptibility heterodimers, was observed when compared either with the patients of group II (pIII textless 0.012) or with healthy individuals (pI textless 10(-6)). On the other hand, in the patients of group II, presenting oligosymptomatic forms and a mean age of 5.7 years at the disease onset, the haplotype combinations encoding in cis or in trans only one DQ (alpha 1*0501, beta 1*0201) heterodimer were significantly increased in comparison either with the patients of group I (pIII textless 0.026) or with controls (pII textless 10(-6)). These findings suggest that a double dose of DQA1*0501, DQB1*0201 genes may predispose a person to an earlier onset and to more severe disease manifestations. Genotype analysis showed that only three patients (all in group I) failed to form in trans or in cis the DQ (alpha 1*0501, beta 1*0201) heterodimer and carried the DQA1*0101,DQB1*0501 haplotype, suggesting its possible role in CD susceptibility. In addition, a significant increment of DQB1*0501 gene (pc textless 0.0065) was found comparing the frequency of DQB1 alleles in CD patients and healthy controls, after exclusion of DQB1*0201 chromosomes.(ABSTRACT TRUNCATED AT 250 WORDS)},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cucca_combinations_1993,

title = {Combinations of specific DRB1, DQA1, DQB1 haplotypes are associated with insulin-dependent diabetes mellitus in Sardinia.},

author = {Cucca, F. and Muntoni, F. and Lampis, R. and Frau, F. and Argiolas, L. and Silvetti, M. and Angius, E. and Cao, A. and De Virgiliis, S. and Congia, M.},

issn = {0198-8859 0198-8859},

year  = {1993},

date = {1993-06-01},

journal = {Hum Immunol},

volume = {37},

number = {2},

pages = {85--94},

abstract = {The Sardinian population has an extremely high incidence of IDDM (30.2 of 100.000 in the age group of 0-14 years). This study reports the molecular characterization of HLA class II genes in 120 IDDM sporadic patients and 89 healthy subjects of Sardinian origin. Compared with other Caucasians, both Sardinian patients and controls had an unusual distribution of haplotypes and genotypes. In particular, there was a high gene frequency of the DRB1*0301, DQA1*0501, DQB1*0201 susceptibility haplotype both in patients (0.58) and controls (0.23) while a reduction of the DRB1*1501, DQA1*0102, DQB1*0602 protective haplotype (0.03) was observed in the healthy population. This distribution may partially explain the high incidence of IDDM reported in Sardinia. The analysis of the DQ beta 57 and DQ alpha 52 residues showed that the absence of Asp 57 and the presence of Arg 52 were associated with IDDM in a dose-response manner. On the other hand, we found that (a) a very similar distribution of these residues was found when comparing Sardinians with another healthy Caucasian population from the same latitude but with a lower rate of IDDM incidence; (b) several genotypes encoding the identical DQ alpha 52/DQ beta 57 phenotype carried very different relative risks; and (c) the DRB1*0403, DQA1*0301, DQB1*0304 haplotype (DQ beta 57 Asp-neg and DQ alpha 52 Arg-pos) was found in 40% of the DR4-positive controls but not in patients (p = 0.00034), while the DRB1*0405, DQA1*0301, and DQB1*0302 haplotype carrying the same residues at the same positions was found in 70% of the DR4-positive patients and in only one control (p = 0.00003). These findings suggest that IDDM susceptibility cannot be completely explained by the model in which only DQ alpha 52 and DQ beta 57 residues are taken into account.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cucca_novel_1993,

title = {A novel HLA-DQB1 allele: evidence for gene conversion event promoted by chi-like sequence at DQB1 locus.},

author = {Cucca, F. and Muntoni, F. and Lampis, R. and Frau, F. and Cao, A. and De Virgiliis, S. and Congia, M.},

issn = {0001-2815 0001-2815},

year  = {1993},

date = {1993-05-01},

journal = {Tissue Antigens},

volume = {41},

number = {5},

pages = {263--266},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{congia_high_1992,

title = {A high frequency of the A30, B18, DR3, DRw52, DQw2 extended haplotype in Sardinian celiac disease patients: further evidence that disease susceptibility is conferred by DQ A1*0501, B1*0201.},

author = {Congia, M. and Frau, F. and Lampis, R. and Frau, R. and Mele, R. and Cucca, F. and Muntoni, F. and Porcu, S. and Boi, F. and Contu, L.},

issn = {0001-2815 0001-2815},

year  = {1992},

date = {1992-02-01},

journal = {Tissue Antigens},

volume = {39},

number = {2},

pages = {78--83},

abstract = {This study characterizes by serological and molecular methods the HLA class I and class II alleles in a group of celiac disease children, their parents and a control group of Sardinian descent. We found the DR3-DQw2 haplotype in all patients which was, in almost all cases (84%), associated with the HLA-A30, B18, DR3, DRw52, DQw2 extended haplotype named "Sardinian haplotype" because of its frequency (12-15%) in this Caucasian population. This is the first time that this DQw2-linked haplotype has been reported with such a high frequency in CD. However, no different distribution of "Sardinian haplotype" was found comparing CD patients with 91 haplotyped DQw2-positive controls. This finding indicates that the DQw2 antigen in Sardinians is almost always associated with the A30, B18, DR3, DRw52, DQw2 extended haplotype. The DQA1 and DQB1 second exon sequence analysis of the B18,DR3 and B8,DR3 haplotypes showed the DQA1*0501 and DQB1*0201 alleles which shared the already published sequences. DPB1 subtyping showed the DPB1*0301 allele more frequently (p less than 0.005) in CD patients but this difference was no longer significant when patients and controls, both heterozygous for the DR3-DQw2 haplotype, were compared. We suggest that the divergent HLA extended haplotypes and DP allele associated with CD, described in different Caucasian populations, can be explained by the particular DQw2 linkage disequilibrium in each population.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{muntoni_hla_1992,

title = {The HLA DQB1*0502 allele is neutrally associated with insulin-dependent diabetes mellitus in the Sardinian population.},

author = {Muntoni, F. and Congia, M. and Cucca, F. and Cossu, P. and Porcu, S. and Frau, F. and Arnone, M. and Songini, M. and Muntoni, S. and Cao, A.},

issn = {0001-2815 0001-2815},

year  = {1992},

date = {1992-01-01},

journal = {Tissue Antigens},

volume = {39},

number = {5},

pages = {262--265},

abstract = {In the Sardinian population a very high incidence of insulin-dependent diabetes mellitus (IDDM) and the lack of HLA-DR2 protective effect due to the high frequency of the A2, Cw7, B17, 3F31, DR2, DQw1 extended haplotype has been reported. This haplotype, carrying a Serine at position 57 of the DQB1*0502 allele, has been previously reported to be underrepresented in patients when compared to controls. In order to provide an explanation for this finding, we defined by RFLP analysis the HLA haplotype of 45 Sardinian IDDM patients and 49 controls. All DR-2DQw1 subjects were molecularly characterized at the HLA DQA and DQB loci. All DR2-positive patients and the vast majority of the DR2-positive controls had the DQB1*0502 allele at the DR2-linked DQB1 locus, with no statistically significant difference between the two groups. All DQA1 genes were the ones expected, with only two exceptions. Nine out of 10 of the DR2-positive patients were compound heterozygotes for DQB1*0201/DQB1*0502 alleles; only this allele combination was significantly increased (p less than 0.0003). Our data suggests that a) the DQB1*0502 allele is neutral for IDDM development and b) the susceptibility to IDDM in our DR2-positive patients is related to the compound heterozygous state between the neutral DQA1*0102/DQB1*0502 and the susceptibility DQA1*0501/DQB1*0201 alleles.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{muntoni_different_1991,

title = {Different HLA DR2-DQw1 haplotypes in Sardinian and northern Italian populations: implications for multiple sclerosis susceptibility.},

author = {Muntoni, F. and Murru, M. R. and Costa, G. and Congia, M. and Cucca, F. and Cossu, P. and Cao, A. and Dessalvi, L. and Pirastu, M. and Marrosu, M. G.},

issn = {0001-2815 0001-2815},

year  = {1991},

date = {1991-07-01},

journal = {Tissue Antigens},

volume = {38},

number = {1},

pages = {34--36},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{de_virgiliis_deferoxamine-induced_1988,

title = {Deferoxamine-induced growth retardation in patients with thalassemia major.},

author = {De Virgiliis, S. and Congia, M. and Frau, F. and Argiolu, F. and Diana, G. and Cucca, F. and Varsi, A. and Sanna, G. and Podda, G. and Fodde, M.},

issn = {0022-3476 0022-3476},

year  = {1988},

date = {1988-10-01},

journal = {J Pediatr},

volume = {113},

number = {4},

pages = {661--669},

abstract = {In the retrospective study reported here, we compared the longitudinal growth in three groups of children with thalassemia major who received a similar transfusion program but different schedules of chelation treatment. In those patients who initiated deferoxamine (DF) administration by daily subcutaneous infusion (50 to 80 mg/kg/day) simultaneously with the beginning of transfusion (at 8 +/- 6 months), mean height at 2 to 6 years of age was significantly reduced in comparison (1) with those patients who initiated DF subcutaneous treatment after 3 years at similar doses and (2) with those who were treated intramuscularly with small doses. In the patients treated at an early stage, those with more marked stunted growth had a clinical and radiologic ricketslike syndrome associated with joint stiffness. Mineral metabolism studies in these patients showed a reduction of hair and leukocyte zinc levels and leukocyte alkaline phosphatase activity. Our findings indicate that DF administration at high doses by continuous infusion before iron overload has been established adversely affects longitudinal growth. By contrast, after 3 years of age, even large doses (in the order of 100/mg/kg/day) did not result in growth retardation. The growth retardation observed may be related to chelation of other trace elements, including zinc, in the presence of low iron burden, to the direct toxic effect of unchelated DF by interference with critical iron-dependent enzymes, or both. These results indicate that in patients with thalassemia major, DF administration should be initiated only after iron accumulation is established, namely, around 3 years of age, after 20 to 30 transfusions, which are usually associated with ferritin levels in the range of 800 to 1000 ng/ml. At this age, deferoxamine doses should be established on the basis of iron balance studies and dose response curves. Doses higher than 50 to 60 mg/kg do not adversely affect growth but produce toxic side effects on acoustic and visual pathways and therefore should not be used. Longitudinal growth monitoring of DF-treated patients is warranted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31497877b,

title = {Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts},

author = {Insa Buers and Ivana Persico and Lara Schöning and Yvonne Nitschke and Maja Di Rocco and Angela Loi and Puneet Kaur Sahi and Gulen Eda Utine and Bilge Bayraktar-Tanyeri and Giuseppe Zampino and Giangiorgio Crisponi and Frank Rutsch and Laura Crisponi},

doi = {10.1111/cge.13639},

issn = {1399-0004},

journal = {Clin Genet},

volume = {97},

number = {1},

pages = {209--221},

abstract = {Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties often leading to sudden death in the neonatal period. The affected individuals who survived the first critical years of life, develop cold-induced sweating and scoliosis in early childhood. The disease is caused by variants in the CRLF1 or in the CLCF1 gene. Both proteins form a heterodimeric complex that acts on cells expressing the ciliary neurotrophic factor receptor (CNTFR). CS/CISS belongs to the family of "CNTFR-related disorders" showing a similar clinical phenotype. Recently, variants in other genes, including KLHL7, NALCN, MAGEL2 and SCN2A, previously linked to other diseases, have been associated with a CS/CISS-like phenotype. Therefore, retinitis pigmentosa and Bohring-Optiz syndrome-like (KLHL7), Congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome (NALCN), Chitayat-Hall/Schaaf-Yang syndrome (MAGEL2), and early infantile epileptic encephalopathy-11 syndrome (SCN2A) all share an overlapping phenotype with CS/CISS, especially in the neonatal period. This review aims to summarize the existing literature on CS/CISS, focusing on the current state of differential diagnosis, pathogenesis and treatment concepts in order to achieve an accurate and rapid diagnosis. This will improve patient management and enable specific treatments for the affected individuals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38981480,

title = {Intestinal Blastocystis is linked to healthier diets and more favorable cardiometabolic outcomes in 56,989 individuals from 32 countries},

author = {Elisa Piperni and Long H Nguyen and Paolo Manghi and Hanseul Kim and Edoardo Pasolli and Sergio Andreu-Sánchez and Alberto Arrè and Kate M Bermingham and Aitor Blanco-Míguez and Serena Manara and Mireia Valles-Colomer and Elco Bakker and Fabio Busonero and Richard Davies and Edoardo Fiorillo and Francesca Giordano and George Hadjigeorgiou and Emily R Leeming and Monia Lobina and Marco Masala and Andrea Maschio and Lauren J McIver and Mauro Pala and Maristella Pitzalis and Jonathan Wolf and Jingyuan Fu and Alexandra Zhernakova and Simone M Cacciò and Francesco Cucca and Sarah E Berry and Danilo Ercolini and Andrew T Chan and Curtis Huttenhower and Tim D Spector and Nicola Segata and Francesco Asnicar},

doi = {10.1016/j.cell.2024.06.018},

issn = {1097-4172},

journal = {Cell},

volume = {187},

number = {17},

pages = {4554--4570.e18},

abstract = {Diet impacts human health, influencing body adiposity and the risk of developing cardiometabolic diseases. The gut microbiome is a key player in the diet-health axis, but while its bacterial fraction is widely studied, the role of micro-eukaryotes, including Blastocystis, is underexplored. We performed a global-scale analysis on 56,989 metagenomes and showed that human Blastocystis exhibits distinct prevalence patterns linked to geography, lifestyle, and dietary habits. Blastocystis presence defined a specific bacterial signature and was positively associated with more favorable cardiometabolic profiles and negatively with obesity (p < 1e-16) and disorders linked to altered gut ecology (p < 1e-8). In a diet intervention study involving 1,124 individuals, improvements in dietary quality were linked to weight loss and increases in Blastocystis prevalence (p = 0.003) and abundance (p < 1e-7). Our findings suggest a potentially beneficial role for Blastocystis, which may help explain personalized host responses to diet and downstream disease etiopathogenesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39076966,

title = {Implications of disease-modifying therapies for multiple sclerosis on immune cells and response to COVID-19 vaccination},

author = {Valeria Orrù and Valentina Serra and Michele Marongiu and Sandra Lai and Valeria Lodde and Magdalena Zoledziewska and Maristella Steri and Annalisa Loizedda and Monia Lobina and Maria Grazia Piras and Francesca Virdis and Giuseppe Delogu and Maria Giuseppina Marini and Maura Mingoia and Matteo Floris and Marco Masala and M Paola Castelli and Rafaela Mostallino and Jessica Frau and Lorena Lorefice and Gabriele Farina and Marzia Fronza and Daniele Carmagnini and Elisa Carta and Silvy Pilotto and Paola Chessa and Marcella Devoto and Paolo Castiglia and Paolo Solla and Roberto Ignazio Zarbo and Maria Laura Idda and Maristella Pitzalis and Eleonora Cocco and Edoardo Fiorillo and Francesco Cucca},

doi = {10.3389/fimmu.2024.1416464},

issn = {1664-3224},

journal = {Front Immunol},

volume = {15},

pages = {1416464},

abstract = {INTRODUCTION: Disease-modifying therapies (DMTs) have been shown to improve disease outcomes in multiple sclerosis (MS) patients. They may also impair the immune response to vaccines, including the SARS-CoV-2 vaccine. However, available data on both the intrinsic immune effects of DMTs and their influence on cellular response to the SARS-CoV-2 vaccine are still incomplete.



METHODS: Here, we evaluated the immune cell effects of 3 DMTs on the response to mRNA SARS-CoV-2 vaccination by comparing MS patients treated with one specific therapy (fingolimod, dimethyl fumarate, or natalizumab) with both healthy controls and untreated patients. We profiled 23 B-cell traits, 57 T-cell traits, and 10 cytokines, both at basal level and after stimulation with a pool of SARS-CoV-2 spike peptides, in 79 MS patients, treated with DMTs or untreated, and 32 healthy controls. Measurements were made before vaccination and at three time points after immunization.



RESULTS AND DISCUSSION: MS patients treated with fingolimod showed the strongest immune cell dysregulation characterized by a reduction in all measured lymphocyte cell classes; the patients also had increased immune cell activation at baseline, accompanied by reduced specific immune cell response to the SARS-CoV-2 vaccine. Also, anti-spike specific B cells progressively increased over the three time points after vaccination, even when antibodies measured from the same samples instead showed a decline. Our findings demonstrate that repeated booster vaccinations in MS patients are crucial to overcoming the immune cell impairment caused by DMTs and achieving an immune response to the SARS-CoV-2 vaccine comparable to that of healthy controls.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28445677,

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

author = {Maristella Steri and Valeria Orrù and M Laura 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 Alarcón 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 Gonçalo 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},

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→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{pmid24074872b,

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 Gonçalo R Abecasis and Edoardo Fiorillo and Serena Sanna and Francesco Cucca},

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

issn = {1097-4172},

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}

}