Sandra D'Alfonso

Publications (47)354.93 Total impact

• Source

  Available from: Viviana Pensato

  Dataset: UBQLN2

  Pamela Milani, Antonia Ratti, Roberto Del Bo, Annachiara Cagnin, Lucia Corrado, Sandra D'Alfonso, Barbara Castellotti, Cinzia Tiloca, Viviana Pensato, Jennifer Agostini, [......], Giacomo Pietro Comi, Giulietta Riboldi, Cristina Cereda, Nicola Ticozzi, Letizia Mazzini, Vincenzo Silani, Cinzia Gellera, Gianni Sorarù, Stefania Corti, Alessandra Bagarotti
• Article: No evidence for a role of rare CYP27B1 functional variations in multiple sclerosis.

  Nadia Barizzone, Ine Pauwels, Bernadetta Luciano, Dean Franckaert, Franca Rosa Guerini, Leentje Cosemans, Kelly Hilven, Alessandro Salviati, James Dooley, Dina Danso-Abeam, Alessia di Sapio, Paola Cavalla, Brigitte Decallonne, Chantal Mathieu, Adrian Liston, Maurizio Leone, Bénédicte Dubois, Sandra D'Alfonso, An Goris
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  ABSTRACT: Association studies have implicated common variants in the 12q14.1 region containing CYP27B1 in multiple sclerosis (MS). Rare CYP27B1 mutations cause autosomal recessive vitamin D-dependent rickets type 1, and it has recently been reported that heterozygous CYP27B1 mutations are associated with increased MS susceptibility and lower active vitamin D levels. By sequencing CYP27B1 in 134 multiplex families and genotyping the most common variant R389H in 2,608 MS patients and 1,987 controls from Italy and Belgium (a total of 4,729 individuals), we were unable to replicate these observations. These results provide evidence against a major role for CYP27B1 mutations in MS. Ann Neurol 2013;
  Annals of Neurology 12/2012; · 11.09 Impact Factor
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  Available from: Cristina Cereda

  Article: Ubiquilin 2 mutations in Italian patients with amyotrophic lateral sclerosis and frontotemporal dementia.

  Cinzia Gellera, Cinzia Tiloca, Roberto Del Bo, Lucia Corrado, Viviana Pensato, Jennifer Agostini, Cristina Cereda, Antonia Ratti, Barbara Castellotti, Stefania Corti, [......], Pamela Milani, Carlo Gabelli, Giulietta Riboldi, Letizia Mazzini, Gianni Sorarù, Sandra D'Alfonso, Franco Taroni, Giacomo Pietro Comi, Nicola Ticozzi, Vincenzo Silani
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  ABSTRACT: OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly involving cortical and spinal motor neurones. Molecular studies have recently identified different mutations in the ubiquilin-2 (UBQLN2) gene as causative of a familial form of X-linked ALS, 90% penetrant in women. The aim of our study was to analyse the UBQLN2 gene in a large cohort of patients with familial (FALS) and sporadic (SALS) amyotrophic lateral sclerosis, with or without frontotemporal dementia (FTD), and in patients with FTD. METHODS: We analysed the UBQLN2 gene in 819 SALS cases, 226 FALS cases, 53 ALS-FTD patients, and 63 patients with a clinical record of FTD. Molecular analysis of the entire coding sequence was carried out in all FALS and ALS-FTD patients, while SALS and FTD patients were analysed specifically for the genomic region coding for the PXX repeat tract. Healthy controls were 845 anonymous blood donors and were screened for the PXX repeat region only. RESULTS: We found five different variants in the UBQLN2 gene in five unrelated ALS patients. Three variants, including two novel ones, involved a proline residue in the PXX repeat region and were found in three FALS cases. The other two were novel variants, identified in one FALS and one SALS patient. None of these variants was present in controls, while one control carried a new heterozygous variant. CONCLUSIONS: Our data support the role of the UBQLN2 gene in the pathogenesis of FALS, being conversely a rare genetic cause in SALS even when complicated by FTD.
  Journal of neurology, neurosurgery, and psychiatry 11/2012; · 4.87 Impact Factor
• Article: Extensive genetics of ALS: A population-based study in Italy.

  Adriano Chiò, Andrea Calvo, Letizia Mazzini, Roberto Cantello, Gabriele Mora, Cristina Moglia, Lucia Corrado, Sandra D'Alfonso, Elisa Majounie, Alan Renton, Fabrizio Pisano, Irene Ossola, Maura Brunetti, Bryan J Traynor, Gabriella Restagno
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  ABSTRACT: OBJECTIVE: To assess the frequency and clinical characteristics of patients with mutations of major amyotrophic lateral sclerosis (ALS) genes in a prospectively ascertained, population-based epidemiologic series of cases. METHODS: The study population includes all ALS cases diagnosed in Piemonte, Italy, from January 2007 to June 2011. Mutations of SOD1, TARDBP, ANG, FUS, OPTN, and C9ORF72 have been assessed. RESULTS: Out of the 475 patients included in the study, 51 (10.7%) carried a mutation of an ALS-related gene (C9ORF72, 32; SOD1, 10; TARDBP, 7; FUS, 1; OPTN, 1; ANG, none). A positive family history for ALS or frontotemporal dementia (FTD) was found in 46 (9.7%) patients. Thirty-one (67.4%) of the 46 familial cases and 20 (4.7%) of the 429 sporadic cases had a genetic mutation. According to logistic regression modeling, besides a positive family history for ALS or FTD, the chance to carry a genetic mutation was related to the presence of comorbid FTD (odds ratio 3.5; p = 0.001), and age at onset ≤54 years (odds ratio 1.79; p = 0.012). CONCLUSIONS: We have found that ∼11% of patients with ALS carry a genetic mutation, with C9ORF72 being the commonest genetic alteration. Comorbid FTD or a young age at onset are strong indicators of a possible genetic origin of the disease.
  Neurology 10/2012; · 8.31 Impact Factor
• Article: Screening of the PFN1 gene in sporadic amyotrophic lateral sclerosis and in frontotemporal dementia.

  Cinzia Tiloca, Nicola Ticozzi, Viviana Pensato, Lucia Corrado, Roberto Del Bo, Cinzia Bertolin, Chiara Fenoglio, Stella Gagliardi, Daniela Calini, Giuseppe Lauria, [......], Letizia Mazzini, Cristina Cereda, Elio Scarpini, Gianni Sorarù, Giacomo P Comi, Sandra D'Alfonso, Cinzia Gellera, Antonia Ratti, John E Landers, Vincenzo Silani
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  ABSTRACT: Mutations in the profilin 1 (PFN1) gene, encoding a protein regulating filamentous actin growth through its binding to monomeric G-actin, have been recently identified in familial amyotrophic lateral sclerosis (ALS). Functional studies performed on ALS-associated PFN1 mutants demonstrated aggregation propensity, alterations in growth cone, and cytoskeletal dynamics. Previous screening of PFN1 gene in sporadic ALS (SALS) cases led to the identification of the p.E117G mutation, which is likely to represent a less pathogenic variant according to both frequency data in control subjects and cases, and functional experiments. To determine the effective contribution of PFN1 mutations in SALS, we analyzed a large cohort of 1168 Italian SALS patients and also included 203 frontotemporal dementia (FTD) cases because of the great overlap between these 2 neurodegenerative diseases. We detected the p.E117G variant in 1 SALS patient and the novel synonymous change p.G15G in another patient, but none in a panel of 1512 control subjects. Our results suggest that PFN1 mutations in sporadic ALS and in FTD are rare, at least in the Italian population.
  Neurobiology of aging 10/2012; · 5.94 Impact Factor
• Article: The role of eight polymorphisms in three candidate genes in determining the susceptibility, phenotype, and response to anti-TNF therapy in patients with rheumatoid arthritis.

  Fulvia Ceccarelli, Sandra D'Alfonso, Carlo Perricone, Yari Carlomagno, Cristiano Alessandri, Cristina Croia, Nadia Barizzone, Carlomaurizio Montecucco, Mauro Galeazzi, Gian Domenico Sebastiani, Giovanni Minisola, Ugo Fiocco, Guido Valesini
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  ABSTRACT: OBJECTIVES: Several single nucleotide polymorphisms (SNPs) have been associated with rheumatoid arthritis (RA) such as peptidylarginine deiminase-4 (PADI4), osteopontin (OPN), and perforin (PRF1) genes. Thus, we aimed at analysing the influence of eight SNPs in these candidate genes on RA susceptibility and their association with laboratory and clinical features in terms of response to anti-TNF therapy. METHODS: We performed a case-control study on 377 Caucasian RA patients and 391 healthy, ethnicity-matched, population-based controls. All subjects were genotyped for PADI4_89/94, PADI4_92, PADI4_104, PADI4_100 in PADI4; -156G/GG and +1239A/C in OPN and A91V and N252S in PRF1 genes. The patients were stratified for shared epitope (SE) HLA-DRB1. rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) were analysed. The patients started anti-TNF treatment and they were evaluated at baseline and after 12 weeks. Disease activity was evaluated with DAS28 and response to treatment with EULAR criteria. RESULTS: A statistically significant association between RA and OPN -156G/GG was found (p=0.023). SE was firmly confirmed to be associated with RA (OR=3.68; p<10-10). No other statistically significant association with clinical and laboratory features were observed. CONCLUSIONS: For the first time, in an Italian cohort, we report the association between -156G/GG in OPN gene and RA susceptibility. Short-term response to anti-TNF therapy was not influenced by the genetic variants studied.
  Clinical and experimental rheumatology 09/2012; · 2.15 Impact Factor
• Article: C9ORF72 repeat expansion in a large Italian ALS cohort: evidence of a founder effect.

  Antonia Ratti, Lucia Corrado, Barbara Castellotti, Roberto Del Bo, Isabella Fogh, Cristina Cereda, Cinzia Tiloca, Carla D'Ascenzo, Alessandra Bagarotti, Viviana Pensato, [......], Mauro Ceroni, Gaia D Oggioni, Kuang Lin, John F Powell, Gianni Sorarù, Nicola Ticozzi, Giacomo P Comi, Sandra D'Alfonso, Cinzia Gellera, Vincenzo Silani
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  ABSTRACT: A hexanucleotide repeat expansion (RE) in C9ORF72 gene was recently reported as the main cause of amyotrophic lateral sclerosis (ALS) and cases with frontotemporal dementia. We screened C9ORF72 in a large cohort of 259 familial ALS, 1275 sporadic ALS, and 862 control individuals of Italian descent. We found RE in 23.9% familial ALS, 5.1% sporadic ALS, and 0.2% controls. Two cases carried the RE together with mutations in other ALS-associated genes. The phenotype of RE carriers was characterized by bulbar-onset, shorter survival, and association with cognitive and behavioral impairment. Extrapyramidal and cerebellar signs were also observed in few patients. Genotype data revealed that 95% of RE carriers shared a restricted 10-single nucleotide polymorphism haplotype within the previously reported 20-single nucleotide polymorphism risk haplotype, detectable in only 27% of nonexpanded ALS cases and in 28% of controls, suggesting a common founder with cohorts of North European ancestry. Although C9ORF72 RE segregates with disease, the identification of RE both in controls and in patients carrying additional pathogenic mutations suggests that penetrance and phenotypic expression of C9ORF72 RE may depend on additional genetic risk factors.
  Neurobiology of aging 07/2012; 33(10):2528.e7-14. · 5.94 Impact Factor
• Source

  Available from: Emoke Endreffy

  Article: Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein.

  Angélica M Delgado-Vega, Mikhail G Dozmorov, Manuel Bernal Quirós, Ying-Yu Wu, Belén Martínez-García, Sergey V Kozyrev, Johan Frostegård, Lennart Truedsson, Enrique de Ramón, María F González-Escribano, [......], Torsten Witte, Bernard R Lauwerys, Emoke Endreffy, László Kovács, Carlos Vasconcelos, Berta Martins da Silva, Jonathan D Wren, Javier Martin, Casimiro Castillejo-López, Marta E Alarcón-Riquelme
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  ABSTRACT: To perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE). Genotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL's test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor κ B (NFkB) binding. Fine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NFκB-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR=2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life. These results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein.
  Annals of the rheumatic diseases 07/2012; 71(7):1219-26. · 8.11 Impact Factor
• Article: The -346T polymorphism of the SH2D1A gene is a risk factor for development of autoimmunity/lymphoproliferation in males with defective Fas function.

  Elena Boggio, Matteo Melensi, Sara Bocca, Annalisa Chiocchetti, Cristoforo Comi, Nausicaa Clemente, Elisabetta Orilieri, Maria Felicia Soluri, Sandra D'Alfonso, Rosella Mechelli, Giovanna Gentile, Alessandro Poggi, Marco Salvetti, Ugo Ramenghi, Umberto Dianzani
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  ABSTRACT: Inherited defects decreasing function of the Fas death receptor cause autoimmune lymphoproliferative syndrome (ALPS) and its variant Dianzani autoimmune lymphoproliferative disease (DALD). Since a deleterious mutation of the SH2D1A gene protects MRLlpr/lpr mice from ALPS development, we investigated the role of SH2D1A, located in the X chromosome, in 51 patients with ALPS or DALD by mutational screening of coding and regulative sequences. Allelic frequency of the -346C>T polymorphism was different in male patients and controls (-346T: 61% vs 36%, p = 0.01), with similar frequencies in ALPS and DALD. By contrast, no differences were found among females or between the controls and patients with multiple sclerosis (229 males, 157 females). Further analyses showed that -346C was a methylation site in CD8(+) T and natural killer cells, and SH2D1A expression was higher in -346T than in -346C males. Finally, in vitro-activated T cells from -346T males produced lower amounts of interferon-γ than those from -346C males. These data suggest that -346T is a predisposing factor for ALPS and DALD in males possibly because of its effect on SAP expression influencing the T-cell response.
  Human immunology 03/2012; 73(5):585-92. · 2.55 Impact Factor
• Article: The impact of osteopontin gene variations on multiple sclerosis development and progression.

  Cristoforo Comi, Giuseppe Cappellano, Annalisa Chiocchetti, Elisabetta Orilieri, Sara Buttini, Laura Ghezzi, Daniela Galimberti, Franca Guerini, Nadia Barizzone, Franco Perla, Maurizio Leone, Sandra D'Alfonso, Domenico Caputo, Elio Scarpini, Roberto Cantello, Umberto Dianzani
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  ABSTRACT: Osteopontin is a proinflammatory molecule, modulating TH1 and TH17 responses. Several reports suggest its involvement in multiple sclerosis (MS) pathogenesis. We previously reported that OPN gene variations at the 3' end are a predisposing factor for MS development and evolution. In this paper, we extended our analysis to a gene variation at the 5' end on the -156G > GG single nucleotide polymorphism (SNP) and replicated our previous findings at the 3' end on the +1239A > C SNP. We found that only +1239A > C SNP displayed a statistically significant association with MS development, but both +1239A > C and -156G > GG had an influence on MS progression, since patients homozygous for both +1239A and -156GG alleles displayed slower progression of disability and slower switch to secondary progression than those carrying +1239C and/or -156G and those homozygous for +1239A only. Moreover, patients homozygous for +1239A also displayed a significantly lower relapse rate than those carrying +1239C, which is in line with the established role of OPN in MS relapses.
  Clinical and Developmental Immunology 01/2012; 2012:212893. · 1.84 Impact Factor
• Article: Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK.

  Casimiro Castillejo-López, Angélica M Delgado-Vega, Jerome Wojcik, Sergey V Kozyrev, Elangovan Thavathiru, Ying-Yu Wu, Elena Sánchez, David Pöllmann, Juan R López-Egido, Serena Fineschi, [......], Johan Frostegård, Bernardo A Pons-Estel, Sandra D'Alfonso, Torsten Witte, José Luis Callejas, John B Harley, Patrick M Gaffney, Javier Martin, Joel M Guthridge, Marta E Alarcón-Riquelme
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  ABSTRACT: Altered signalling in B cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterise the role of BANK1 and BLK in SLE, a genetic interaction analysis was performed hypothesising that genetic interactions could reveal functional pathways relevant to disease pathogenesis. The GPAT16 method was used to analyse the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK. Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could also show a protein-protein interaction was tested. The co-immunoprecipitation and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and primary naive B cells endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies. This study shows a genetic interaction between BANK1 and BLK, and demonstrates that these molecules interact physically. The results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signalling pathway.
  Annals of the rheumatic diseases 01/2012; 71(1):136-42. · 8.11 Impact Factor
• Article: Novel association of acid phosphatase locus 1*C allele with systemic lupus erythematosus.

  María Teruel, Jose-Ezequiel Martin, Norberto Ortego-Centeno, Juan Jiménez-Alonso, Julio Sánchez-Román, Enrique de Ramón, M Francisca Gonzalez-Escribano, Bernardo A Pons-Estel, Sandra D'Alfonso, Gian Domenico Sebastiani, Torsten Witte, Nunzio Bottini, Miguel A González-Gay, Marta E Alarcón-Riquelme, Javier Martin
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  ABSTRACT: The red cell acid phosphatase (ACP1) gene, which encodes a low-molecular-weight phosphotyrosine phosphatase, has been suggested as a common genetic factor of autoimmunity. In the present study, we aim to investigate the possible association of ACP1 with the susceptibility of systemic lupus erythematosus (SLE). A total of 1,546 SLE patients and 1,947 healthy individuals from 4 Caucasians populations were included in the present study. Four single-nucleotide polymorphisms (SNPs) were genotyped in this study: rs10167992, rs11553742, rs7576247, and rs3828329. ACP1*A, ACP1*B, and ACP1*C codominant ACP1 alleles were determined using 2 of the SNPs and analyzed. After the meta-analysis test was performed, a significant association of rs11553742*T was observed (p(pooled) = 0.005, odds ratios = 1.37 [1.10-1.70]), retaining significance after multiple testing was applied (p(FDR) = 0.019). Our data indicate for first time the association of rs11553742*T with increased susceptibility in SLE patients.
  Human immunology 10/2011; 73(1):107-10. · 2.55 Impact Factor
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  Available from: Federica Esposito

  Article: Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

  Stephen Sawcer, Garrett Hellenthal, Matti Pirinen, Chris C A Spencer, Nikolaos A Patsopoulos, Loukas Moutsianas, Alexander Dilthey, Zhan Su, Colin Freeman, Sarah E Hunt, [......], Jan Hillert, Adrian J Ivinson, Philip L De Jager, Leena Peltonen, Graeme J Stewart, David A Hafler, Stephen L Hauser, Gil McVean, Peter Donnelly, Alastair Compston
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  ABSTRACT: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
  Nature 08/2011; 476(7359):214-9. · 36.28 Impact Factor
• Article: Association of osteopontin regulatory polymorphisms with systemic sclerosis.

  Nadia Barizzone, Maurizio Marchini, Francesca Cappiello, Annalisa Chiocchetti, Elisabetta Orilieri, Daniela Ferrante, Lucia Corrado, Simona Mellone, Raffaella Scorza, Umberto Dianzani, Sandra D'Alfonso
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  ABSTRACT: To test the involvement of osteopontin gene (OPN) in systemic sclerosis (SSc) susceptibility, two OPN single nucleotide polymorphisms previously reported to be associated with systemic lupus erythematosus, namely -156G/GG (proximal promoter) and +1239A/C (3' untranslated region (UTR)), were tested in 357 Italian patients and 864 matched control subjects. OPN serum levels were determined by enzyme-linked immunosorbent assay in 32 patients and 116 controls. Compared with the controls, in SSc patients there was a significantly increased frequency of the alleles -156G (p = 0.0086), and +1239C (p = 0.00064), paralleling the association reported for systemic lupus erythematosus. According to logistic regression analysis, this association is primarily due to the effect of +1239 single nucleotide polymorphism. OPN serum levels were significantly higher in SSc patients than in controls (p = 0.00025). These data suggest that OPN genetic variations have a role in SSc susceptibility, reporting for the first time an involvement of this molecule in SSc pathogenesis and emphasizing that SSc shares pathogenetic mechanisms with other autoimmune diseases.
  Human immunology 07/2011; 72(10):930-4. · 2.55 Impact Factor
• Article: ATXN-2 CAG repeat expansions are interrupted in ALS patients.

  Lucia Corrado, Letizia Mazzini, Gaia Donata Oggioni, Bernadetta Luciano, Michela Godi, Alfredo Brusco, Sandra D'Alfonso
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  ABSTRACT: It has recently been suggested that short expansions of CAG repeat in the gene ATXN-2 causing SCA2 (spinocerebellar ataxia type 2) are associated with an increased risk of amyotrophic lateral sclerosis (ALS) in the populations of the USA and northern Europe. In this study, we investigated the role of ATXN-2 in Italian patients clinically diagnosed with ALS and characterized the molecular structure of ATXN-2 expansions. We assessed the size of the CAG repeat in ATXN-2 exon 1 in 232 Italian ALS patients and 395 matched controls. ATXN-2 expanded alleles containing > 30 repeats have been observed in seven sporadic ALS patients (3.0%), while being absent in the controls (p = 0.00089). Four out of the seven patients had an ATXN-2 allele in the intermediate-fully pathological range: one with 32 repeats, 2 with 33 repeats and 1 with 37 repeats, accounting for 1.7% of the ALS cohort. Sequencing of expanded (> 32) alleles showed that they were all interrupted with at least one CAA triplet. ATXN-2 alleles with the same length and structure have been reported in SCA2 patients with parkinsonism or in familial and sporadic Parkinson. Conversely, the phenotype of the present patients was typically ALS with no signs or symptoms of ataxia or parkinsonism. In conclusion, the findings of ATXN-2 expansions in pure ALS cases suggest that ALS may be a third phenotype (alongside ataxia/parkinsonism and pure Parkinson) associated with ATXN-2 interrupted alleles.
  Human Genetics 05/2011; 130(4):575-80. · 5.07 Impact Factor
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  Available from: Maurizio Leone

  Article: Association of HLA class I markers with multiple sclerosis in the Italian and UK population: evidence of two independent protective effects.

  Laura Bergamaschi, Maria Ban, Nadia Barizzone, Maurizio Leone, Daniela Ferrante, Maria Edvige Fasano, Franca R Guerini, Lucia Corrado, Paola Naldi, Ennia Dametto, [......], Rosella Mechelli, Daniela Galimberti, Elio Scarpini, Paola Cavalla, Valeria Bargiggia, Domenico Caputo, Susanna Cordera, Francesco Monaco, Patricia Momigliano-Richiardi, Sandra D'Alfonso
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  ABSTRACT: The association of HLA A*02 with multiple sclerosis (MS) was recently confirmed by the authors, and it was observed that the combined presence of HLA Cw*05 significantly enhanced (threefold) the protective effect of HLA A*02. Since A*02-Cw*05 is carried by two HLA extended haplotypes characterised by the B*4402 and B*1801 alleles, respectively, the association analysis was extended to HLA B*44 and B*18 in an Italian sample (1445 MS cases and 973 controls) and these associations were verified in a UK cohort (721 MS cases, 408 controls and 480 family trios). A strong protective effect, independent of DR15, of the A*02-Cw*05 combination carrying B*44 (OR 0.27, p=3.3×10(-5)) was seen in the Italian samples and confirmed in UK family trios (OR 0.33, p=5.5×10(-4)) and in a combined cohort of UK families and case-controls (OR 0.53, p=0.044). This protective effect was significantly stronger than that mediated by A*02 alone. Logistic regression showed that A*02-Cw*05 maintained a significant protection when adjusted for B alleles (Italy: OR 0.38, p=6.5×10(-7); UK: OR 0.60, p=0.0029), indicating that it was not secondary to linkage disequilibrium with B*44. Different from A*02, the other HLA class I tested markers individually showed no significant (Cw*05, B*18) or a modest (B*44) protection when adjusted for the remaining markers. This study identified at least two independent protective effects which are tagged by A*02-Cw*05 and A*02, respectively. Further studies are needed to elucidate whether this protective effect is due to the presence of an unanalysed factor characterising the HLA extended haplotype(s) carrying A*02 and Cw*05 or to a direct interaction between these alleles.
  Journal of Medical Genetics 03/2011; 48(7):485-92. · 6.36 Impact Factor
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  Available from: Manuel Calaza

  Article: Association of systemic lupus erythematosus clinical features with European population genetic substructure.

  Elisa Alonso-Perez, Marian Suarez-Gestal, Manuel Calaza, Torsten Witte, Chryssa Papasteriades, Maurizio Marchini, Sergio Migliaresi, Attila Kovacs, Josep Ordi-Ros, Marc Bijl, [......], Sarka Ruzickova, Rudolf Pullmann, Patricia Carreira, Fotini N Skopouli, Sandra D'Alfonso, Gian Domenico Sebastiani, Ana Suarez, Francisco J Blanco, Juan J Gomez-Reino, Antonio Gonzalez
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  ABSTRACT: Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (P = 6.8×10(-4)), oral ulcers (P = 6.9×10(-4)) and photosensitivity (P = 0.002). Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested.
  PLoS ONE 01/2011; 6(12):e29033. · 4.09 Impact Factor
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  Available from: Marco Zucchelli

  Article: Multiple polymorphisms affect expression and function of the neuropeptide S receptor (NPSR1).

  Francesca Anedda, Marco Zucchelli, Danika Schepis, Anna Hellquist, Lucia Corrado, Sandra D'Alfonso, Adnane Achour, Gerald McInerney, Alejandro Bertorello, Mikael Lördal, Ragnar Befrits, Jan Björk, Francesca Bresso, Leif Törkvist, Jonas Halfvarson, Juha Kere, Mauro D'Amato
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  ABSTRACT: neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02). we identified one promoter SNP (rs2530547 [-103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk. these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.
  PLoS ONE 01/2011; 6(12):e29523. · 4.09 Impact Factor
• Article: A 3'-untranslated region variant is associated with impaired expression of CD226 in T and natural killer T cells and is associated with susceptibility to systemic lupus erythematosus.

  Sara E Löfgren, Angelica M Delgado-Vega, Caroline J Gallant, Elena Sánchez, Johan Frostegård, Lennart Truedsson, Enrique de Ramón Garrido, José M Sabio, María F González-Escribano, Bernardo A Pons-Estel, Sandra D'Alfonso, Torsten Witte, Bernard R Lauwerys, Emoke Endreffy, László Kovács, Carlos Vasconcelos, Berta Martins da Silva, Javier Martín, Marta E Alarcón-Riquelme, Sergey V Kozyrev
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  ABSTRACT: Costimulatory receptor CD226 plays an important role in T cell activation, differentiation, and cytotoxicity. This study was undertaken to investigate the genetic association of CD226 with susceptibility to systemic lupus erythematosus (SLE) and to assess the functional implications of this association. Twelve tag single-nucleotide polymorphisms (SNPs) in CD226 were typed in 1,163 SLE patients and 1,482 healthy control subjects from Europe or of European ancestry. Analyses of association were performed by single-marker Cochran-Mantel-Haenszel meta-analysis, followed by haplotype analysis. Gene expression was analyzed by quantitative real-time polymerase chain reaction analyses of RNA from peripheral blood mononuclear cells, and by fluorescence-activated cell sorter analysis. To study the functional impact of the associated variants, luciferase reporter constructs containing different portions of the 3'-untranslated region (3'-UTR) of the gene were prepared and used in transfection experiments. A 3-variant haplotype, rs763361;rs34794968;rs727088 (ATC), in the last exon of CD226 was associated with SLE (P = 1.3 × 10(-4) , odds ratio 1.24, 95% confidence interval 1.11-1.38). This risk haplotype correlated with low CD226 transcript expression and low CD226 protein levels on the surface of CD4+ and CD8+ T cells and natural killer T (NKT) cells. NK cells expressed high levels of CD226, but this expression was independent of the haplotype. Reporter assays with deletion constructs indicated that only the presence of rs727088 could account for the differences in the levels of luciferase transcripts. This study identified an association of CD226 with SLE in individuals of European ancestry. These data support the importance of the 3'-UTR SNP rs727088 in the regulation of CD226 transcription both in T cells and in NKT cells.
  Arthritis & Rheumatism 11/2010; 62(11):3404-14. · 7.87 Impact Factor
• Source

  Available from: Maurizio Leone

  Article: Association of the CBLB gene with multiple sclerosis: new evidence from a replication study in an Italian population.

  Lucia Corrado, Laura Bergamaschi, Nadia Barizzone, Maria Edvige Fasano, Franca R Guerini, Marco Salvetti, Daniela Galimberti, Maria Donata Benedetti, Maurizio Leone, Sandra D'Alfonso
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  ABSTRACT: The T allele of rs9657904 within the CBLB gene was recently found to be significantly associated with multiple sclerosis (MS) in a genome-wide association study in Sardinia. To replicate this association in an independent population with a different genetic background. The rs9657904 variant was typed in a sample of 1435 cases and 1466 controls from the Italian mainland. It was found that in this sample also, the common allele T of rs9657904 is significantly positively associated (one-tailed p=7.35 × 10(-5)) and with a comparable effect size with MS (OR=1.31, 95% CI 1.14 to 1.52). These data provide further evidence of the association of MS disease with variation within CBLB.
  Journal of Medical Genetics 10/2010; 48(3):210-1. · 6.36 Impact Factor