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1. Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants

Author

Juran BD, Hirschfield GM, Invernizzi P, Atkinson EJ, Li Y, Xie G, Kosoy R, Ransom M, Sun Y, Bianchi I, Schlicht EM, Lleo A, Coltescu C, Bernuzzi F, Podda M, Lammert C, Shigeta R, Chan LL, Balschun T, Marconi M, Cusi D, Heathcote EJ, Mason AL, Myers RP, Milkiewicz P, Odin JA, Luketic VA, Bacon BR, Bodenheimer HC Jr, Liakina V, Vincent C, Levy C, Franke A, Gregersen PK, Bossa F, Gershwin ME, deAndrade M, Amos CI, Italian PBC Genetics Study Group, Lazaridis KN, Seldin MF, Siminovitch KA, Almasio PL, Alvaro D, Andriulli A, Barlassina C, Battezzati PM, Benedetti A, Bragazzi M, Brunetto M, Bruno S, Caliari L, Casella G, Civardi F, Coco B, Colli A, Colombo M, Colombo S, Cursaro C, Crocè LS, Crosignani A, Donato F, Fabris L, Ferrari C, Floreani A, Fontana R, Galli A, Grattagliano I, Lazzari R, Macaluso F, Malinverno F, Marra F, Marzioni M, Mascia E, Mattalia A, Montanari R, Morini L, Morisco F, Niro GA, Picciotto A, Portincasa P, Prati D, Rosina F, Rossi S, Selmi C, Spinzi G, Strazzabosco M, Tarallo S, Tiribelli C, Toniutto P, Vinci M, Zuin M., ANDREONE, PIETRO, MURATORI, LUIGI, MURATORI, PAOLO, Juran BD, Hirschfield GM, Invernizzi P, Atkinson EJ, Li Y, Xie G, Kosoy R, Ransom M, Sun Y, Bianchi I, Schlicht EM, Lleo A, Coltescu C, Bernuzzi F, Podda M, Lammert C, Shigeta R, Chan LL, Balschun T, Marconi M, Cusi D, Heathcote EJ, Mason AL, Myers RP, Milkiewicz P, Odin JA, Luketic VA, Bacon BR, Bodenheimer HC Jr, Liakina V, Vincent C, Levy C, Franke A, Gregersen PK, Bossa F, Gershwin ME, deAndrade M, Amos CI, Italian PBC Genetics Study Group, Lazaridis KN, Seldin MF, Siminovitch KA, Almasio PL, Alvaro D, Andreone P, Andriulli A, Barlassina C, Battezzati PM, Benedetti A, Bragazzi M, Brunetto M, Bruno S, Caliari L, Casella G, Civardi F, Coco B, Colli A, Colombo M, Colombo S, Cursaro C, Crocè LS, Crosignani A, Donato F, Fabris L, Ferrari C, Floreani A, Fontana R, Galli A, Grattagliano I, Lazzari R, Macaluso F, Malinverno F, Marra F, Marzioni M, Mascia E, Mattalia A, Montanari R, Morini L, Morisco F, Muratori L, Muratori P, Niro GA, Picciotto A, Portincasa P, Prati D, Rosina F, Rossi S, Selmi C, Spinzi G, Strazzabosco M, Tarallo S, Tiribelli C, Toniutto P, Vinci M, Zuin M., Juran, Bd, Hirschfield, Gm, Invernizzi, P, Atkinson, Ej, Li, Y, Xie, G, Kosoy, R, Ransom, M, Sun, Y, Bianchi, I, Schlicht, Em, Lleo, A, Coltescu, C, Bernuzzi, F, Podda, M, Lammert, C, Shigeta, R, Chan, Ll, Balschun, T, Marconi, M, Cusi, D, Heathcote, Ej, Mason, Al, Myers, Rp, Milkiewicz, P, Odin, Ja, Luketic, Va, Bacon, Br, Bodenheimer HC, Jr, Liakina, V, Vincent, C, Levy, C, Franke, A, Gregersen, Pk, Bossa, F, Gershwin, Me, Deandrade, M, Amos, Ci, Lazaridis, Kn, Seldin, Mf, Siminovitch, Ka, Morisco, Filomena, Italian PBC Genetics Study, Group, Juran, B, Hirschfield, G, Atkinson, E, Schlicht, E, Chan, L, Heathcote, E, Mason, A, Myers, R, Odin, J, Luketic, V, Bacon, B, Bodenheimer, H, Gregersen, P, Gershwin, M, Amos, C, Italian PBC Genetics Study, G, Lazaridis, K, Seldin, M, Siminovitch, K, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Civardi, F, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Crocè, L, Crosignani, A, Donato, F, Fabris, L, Ferrari, C, Floreani, A, Fontana, R, Galli, A, Grattagliano, I, Lazzari, R, Macaluso, F, Malinverno, F, Marra, F, Marzioni, M, Mascia, E, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Portincasa, P, Prati, D, Rosina, F, Rossi, S, Selmi, C, Spinzi, G, Strazzabosco, M, Tarallo, S, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, Almasio, Pl, Battezzati, Pm, Croce', Saveria, Niro, Ga, Tiribelli, Claudio, and Zuin, M.

Subjects
MULTILOCUS GENOTYPE DATA, PRIMARY BILIARY CIRRHOSIS, PBC, 0302 clinical medicine, Gene Frequency, MED/12 - GASTROENTEROLOGIA, HLA Antigens, REGULATORY T-CELLS, RHEUMATOID-ARTHRITIS, VITAMIN-D, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Genetics, CLASSICAL HLA ALLELES, 0303 health sciences, Liver Cirrhosis, Biliary, PBC, HLA alleles, Association Studies Articles, CELIAC-DISEASE, General Medicine, GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY LOCI, GENETIC RISK, 3. Good health, Chromosomes, Human, Pair 1, SINGLE NUCLEOTIDE POLYMORPHISMS, 030211 gastroenterology & hepatology, Chromosomes, Human, Pair 7, GENETIC ANALYSES, Genotype, Single-nucleotide polymorphism, Locus (genetics), Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Humans, SNP, Genetic Predisposition to Disease, Allele, Molecular Biology, Allele frequency, Alleles, 030304 developmental biology, Chromosomes, Human, Pair 13, Haplotype, Epistasis, Genetic, Genetic Loci, Case-Control Studies, Imputation (genetics)
Abstract

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.

Published
2012

2. Pathway-based analysis of primary biliary cirrhosis genome-wide association studies

Author

Kar, Sp, Seldin, Mf, Chen, W, Lu, E, Hirschfield, Gm, Invernizzi, P, Heathcote, J, Cusi, D, Almasio, Pl, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Croce, Ls, Crosignani, A, Donato, F, Elia, G, Fabris, L, Floreani, A, Galli, A, Grattagliano, I, Lazzari, R, Lleo, A, Macaluso, F, Marra, F, Marzioni, M, Mascia, E, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, Picciotto, A, Podda, M, Portincasa, P, Prati, D, Raggi, C, Rosina, F, Rossi, S, Sogno, I, Spinzi, G, Strazzabosco, M, Tarallo, Sonia, Tarocchi, M, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, Gershwin, Me, Siminovitch, Ka, Amos, Ci, Tarallo, S, Zuin, M., S. P., Kar, M. F., Seldin, W., Chen, E., Lu, G. M., Hirschfield, P., Invernizzi, J., Heathcote, D., Cusi, t. I., Pbc, P. L., Almasio, D., Alvaro, P., Andreone, A., Andriulli, C., Barlassina, A., Benedetti, F., Bernuzzi, I., Bianchi, M., Bragazzi, M., Brunetto, S., Bruno, L., Caliari, G., Casella, B., Coco, A., Colli, M., Colombo, S., Colombo, C., Cursaro, Croce', Saveria, A., Crosignani, F., Donato, G., Elia, L., Fabri, A., Floreani, A., Galli, I., Grattagliano, R., Lazzari, A., Lleo, F., Macaluso, F., Marra, M., Marzioni, E., Mascia, A., Mattalia, R., Montanari, L., Morini, F., Morisco, L., Muratori, P., Muratori, G., Niro, A., Picciotto, M., Podda, P., Portincasa, D., Prati, C., Raggi, F., Rosina, S., Rossi, I., Sogno, G., Spinzi, M., Strazzabosco, S., Tarallo, M., Tarocchi, Tiribelli, Claudio, P., Toniutto, M., Vinci, M., Zuin, M. E., Gershwin, K. A., Siminovitch, C. I., Amos, SP Kar, MF Seldin, W Chen, E Lu, GM Hirschfield, P Invernizzi, J Heathcote, D Cusi, the Italian PBC Genetics Study Group [.., P Andreone, L Muratori, P Muratori, ], ME Gershwin, KA Siminovitch, CI Amos, Kar, S, Seldin, M, Chen, W, Lu, E, Hirschfield, G, Invernizzi, P, Heathcote, J, Cusi, D, the Italian PBC Genetics Study, G, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, M, Brunetto, M, Bruno, S, Caliari, L, Casella, G, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Croce, L, Crosignani, A, Donato, F, Elia, G, Fabris, L, Floreani, A, Galli, A, Grattagliano, I, Lazzari, R, Lleo, A, Macaluso, F, Marra, F, Marzioni, M, Mascia, E, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G., P, A, Podda, M, Portincasa, P, Prati, D, Raggi, C, Rosina, F, Rossi, S, Sogno, I, Spinzi, G, Strazzabosco, M, Tarallo, S, Tarocchi, M, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, M, Gershwin, M, Siminovitch, K, Amos, C, Kar, Sp, Seldin, Mf, Hirschfield, Gm, Almasio, Pl, Morisco, Filomena, Niro, G, Picciotto, A, Gershwin, Me, Siminovitch, Ka, Amos, Ci, and the Italian PBC Genetics Study, Group

Subjects
Male, Linkage disequilibrium, PRIMARY BILIARY CIRRHOSIS, Genome-wide association study, VARIANTS, Linkage Disequilibrium, Cohort Studies, ACTIVATION, Primary biliary cirrhosis, Gene Frequency, MED/12 - GASTROENTEROLOGIA, Databases, Genetic, SENSORS, Genetics (clinical), Genetics, Liver Cirrhosis, Biliary, Middle Aged, EPITHELIAL-MESENCHYMAL TRANSITION, hedgehog signaling, Hedgehog signaling pathway, Algorithm, Italy, DISEASES, Female, Algorithms, TRAITS, Human, Signal Transduction, Canada, Genotype, Immunology, EPITHELIAL-MESENCHYMAL TRANSITION, CELLS, ACTIVATION, GENE, IDENTIFICATION, RESPONSES, VARIANTS, DISEASES, SENSORS, TRAITS, autoimmune disease, Biology, Polymorphism, Single Nucleotide, linear combination test, Article, Autoimmune Diseases, Meta-Analysis as Topic, medicine, Humans, Genetic Predisposition to Disease, phosphatidylinositol signaling, KEGG, Allele frequency, Genetic association, IDENTIFICATION, medicine.disease, GENE, Multiple comparisons problem, PBC, genome wide association, CELLS, Cohort Studie, Genome-Wide Association Study, RESPONSES
Abstract

Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P

Published
2013

3. Contribution of Rare and Low-Frequency Variants to Multiple Sclerosis Susceptibility in the Italian Continental Population

Author

Ferdinando Clarelli, Nadia Barizzone, Eleonora Mangano, Miriam Zuccalà, Chiara Basagni, Santosh Anand, Melissa Sorosina, Elisabetta Mascia, Silvia Santoro, PROGEMUS, PROGRESSO, Franca Rosa Guerini, Eleonora Virgilio, Antonio Gallo, Alessandro Pizzino, Cristoforo Comi, Vittorio Martinelli, Giancarlo Comi, Gianluca De Bellis, Maurizio Leone, Massimo Filippi, Federica Esposito, Roberta Bordoni, Filippo Martinelli Boneschi, Sandra D'Alfonso, P Crociani, D Vecchio, P Ragonese, A Gajofatto, E Scarpini, A Bertolotto, D Caputo, C Gasperini, F Granella, S Cordera, P Cavallo, R Cavallo, R Bergamaschi, G Ristori, C Solaro, F Martinelli, F Passantino, M Pugliatti, A Gallo, L Brambilla, C Clerico, F Capone, F Esposito, G Liberatore, M Rodegher, p Rossi, M Radaelli, L Moiola, B Colombo, A Ghezzi, A Annovazzi, R Capra, G Coniglio, M. P Amato, B Nacmias, G Tedeschi, A D’Ambrosio, P Cavalla, F Patti, E D’Amico, D Galimberti, P Gallo, M Atzori, L Grimaldi, S Bucello, G Mancardi, E Capello, Clarelli, F, Barizzone, N, Mangano, E, Zuccalà, M, Basagni, C, Anand, S, Sorosina, M, Mascia, E, Santoro, S, Guerini, Fr, Virgilio, E, Gallo, A, Pizzino, A, Comi, C, Martinelli, V, Comi, G, De Bellis, G, Leone, M, Filippi, M, Esposito, F, Bordoni, R, Martinelli-Boneschi, F, D’Alfonso, S, Clarelli, F., Barizzone, N., Mangano, E., Zuccala, M., Basagni, C., Anand, S., Sorosina, M., Mascia, E., Santoro, S., Guerini, F. R., Virgilio, E., Gallo, A., Pizzino, A., Comi, C., Martinelli, V., Comi, G., De Bellis, G., Leone, M., Filippi, M., Esposito, F., Bordoni, R., Martinelli Boneschi, F., and D'Alfonso, S.

Subjects
multiple sclerosi, Genetics, rare variants, Molecular Medicine, QH426-470, pool sequencing, multiple sclerosis, burden test, EFCAB13, Genetics (clinical), Original Research
Abstract

Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and in silico functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in EFCAB13, a gene coding for a protein of an unknown function (p < 10–4). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (p = 0.0093 and p = 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (p = 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (p = 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases.

Published
2022

4. An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients

Author

Cristoforo Comi, Filippo Martinelli-Boneschi, Lucia Corrado, Rachele Cagliani, Martina Tosi, Cristina Agliardi, Francesco Favero, Giancarlo Comi, Nadia Barizzone, Melissa Sorosina, Massimo Filippi, Ferdinando Clarelli, Davide Corà, Domenico Caputo, Elisabetta Mascia, Manuela Sironi, Maria Liguori, Chiara Basagni, Vittorio Martinelli, Domizia Vecchio, Miriam Zuccalà, Federica Esposito, Maurizio Leone, Diego Forni, Sandra D'Alfonso, Franca Rosa Guerini, Laura Mendozzi, Barizzone, N., Cagliani, R., Basagni, C., Clarelli, F., Mendozzi, L., Agliardi, C., Forni, D., Tosi, M., Mascia, E., Favero, F., Cora, D., Corrado, L., Sorosina, M., Esposito, F., Zuccala, M., Vecchio, D., Liguori, M., Comi, C., Comi, G., Martinelli, V., Filippi, M., Leone, M., Martinelli-Boneschi, F., Caputo, D., Sironi, M., Guerini, F. R., and D'Alfonso, S.

Subjects
Adult, Male, DNA Copy Number Variations, Genetic Linkage, multiple sclerosis, multiplex families, linkage study, NGS, rare variants, Biology, QH426-470, Article, Multiple sclerosis, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Genetic linkage, Exome Sequencing, medicine, Genetics, Humans, Multiplex, Genetic Predisposition to Disease, Gene, Exome, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, Aged, Linkage study, Whole genome sequencing, Aged, 80 and over, 0303 health sciences, Whole Genome Sequencing, Genome, Human, High-Throughput Nucleotide Sequencing, Rare variants, Heritability, Middle Aged, medicine.disease, Pedigree, Italy, Multiplex families, Female, 030217 neurology & neurosurgery
Abstract

Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes—particularly mRNA transport—or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.

Published
2021
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5. Identification of differential DNA methylation associated with multiple sclerosis: A family-based study

Author

Ferdinando Clarelli, S. Bonfiglio, Massimo Filippi, Federica Esposito, A. Protti, Giulia Barbiera, Filippo Martinelli-Boneschi, Vittorio Martinelli, E. Stupka, Silvia Santoro, Elisabetta Mascia, Clara Guaschino, Francesca Giannese, Melissa Sorosina, Dejan Lazarevic, Jose Manuel Garcia-Manteiga, Davide Cittaro, Garcia-Manteiga, J. M., Clarelli, F., Bonfiglio, S., Mascia, E., Giannese, F., Barbiera, G., Guaschino, C., Sorosina, M., Santoro, S., Protti, A., Martinelli, V., Cittaro, D., Lazarevic, D., Stupka, E., Filippi, M., Esposito, F., and Martinelli-Boneschi, F.

Subjects
0301 basic medicine, Adult, Male, Multiple Sclerosis, Immunology, Genomics, Biology, Epigenesis, Genetic, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Immunology and Allergy, Humans, Multiplex, Epigenetics, Gene, Aged, Genetics, Multiple sclerosis, Methylation, DNA Methylation, Middle Aged, medicine.disease, Pedigree, 030104 developmental biology, Differentially methylated regions, Neurology, Italy, DNA methylation, Female, Neurology (clinical), 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Multiple Sclerosis (MS) is caused by a still unknown interplay between genetic and environmental factors. Epigenetics, including DNA methylation, represents a model for environmental factors to influence MS risk. Twenty-six affected and 26 unaffected relatives from 8 MS multiplex families were analysed in a multicentric Italian study using MeDIP-Seq, followed by technical validation and biological replication in two additional families of differentially methylated regions (DMRs) using SeqCap Epi Choice Enrichment kit (Roche®). Associations from MeDIP-Seq across families were combined with aggregation statistics, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypo-methylated regions, which point to NTM and BAI3 genes, and to 2 hyper-methylated regions in PIK3R1 and CAPN13. These 4 novel regions contain genes of potential interest that need to be tested in larger cohorts of patients.

Published
2021

6. Pharmacogenetic study of long-term response to interferon-β treatment in multiple sclerosis

Author

Federica Esposito, Giuseppe Liberatore, Bruno Colombo, Ana Maria Osiceanu, Elisabetta Mascia, Melissa Sorosina, Giulia Pavan, Silvia Santoro, Ferdinando Clarelli, F. Martinelli-Boneschi, Lucia Moiola, Giancarlo Comi, Vittorio Martinelli, Clarelli, F., Liberatore, G., Sorosina, M., Osiceanu, A. M., Esposito, F., Mascia, E., Santoro, S., Pavan, G., Colombo, B., Moiola, L., Martinelli, V., Comi, Giancarlo, and Martinelli boneschi, F.

Subjects
0301 basic medicine, Male, Time Factors, Pharmacogenomic Variants, Genome-wide association study, Bioinformatics, Receptors, Metabotropic Glutamate, Pharmacogenetic Study, 0302 clinical medicine, Immunologic Factor, Receptors, Kainic Acid, Multiple Sclerosi, Pharmacogenetic, Middle Aged, Phenotype, Treatment Outcome, Italy, Pharmacogenomic Variant, Molecular Medicine, Female, Case-Control Studie, Human, Adult, Multiple Sclerosis, Time Factor, Adolescent, Genotype, Cell Adhesion Molecules, Neuronal, Quantitative Trait Loci, Quantitative trait locus, Biology, Peripheral blood mononuclear cell, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Genetic, Genetics, medicine, Humans, Immunologic Factors, Allele, Pharmacology, Multiple sclerosis, Gene Expression Profiling, Interferon-beta, medicine.disease, Pharmacogenomic Testing, Gene expression profiling, 030104 developmental biology, Pharmacogenetics, Case-Control Studies, Immunology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The aim of the study is the identification of genetic factors that influence the long-term response to interferon-β (IFNβ) (4-year follow-up). We performed a genome-wide association study in 337 IFNβ-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNβ-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P

Published
2015

7. Impact of multiple sclerosis risk loci in postinfectious neurological syndromes

Author

Ferdinando Clarelli, Silvia Peroni, Laura Ferrè, Silvia Santoro, Andrea Cortese, Giancarlo Comi, Angelo Gugliemi, Filippo Martinelli-Boneschi, Riccardo Currò, Elisabetta Mascia, Giulia Berzero, Enrico Marchioni, Massimo Filippi, Federica Esposito, Elisa Vegezzi, Ilaria Callegari, Melissa Sorosina, Martinelli-Boneschi, F., Curro, R., Santoro, S., Berzero, G., Sorosina, M., Ferre, L., Mascia, E., Peroni, S., Comi, G., Gugliemi, A., Vegezzi, E., Callegari, I., Filippi, M., Cortese, A., Esposito, F., Clarelli, F., and Marchioni, E.

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Genotype, Myelitis, Single-nucleotide polymorphism, Disease, Postinfectious neurological syndrome, Multiple sclerosis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Genetics, Humans, 030212 general & internal medicine, Genetic variability, Alleles, Acquired demyelinating disease, business.industry, Retrospective cohort study, General Medicine, Syndrome, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Neurology, Female, Neurology (clinical), Differential diagnosis, business, 030217 neurology & neurosurgery, Cohort study, Weighted genetic risk score
Abstract

Background: The genetic component of multiple sclerosis (MS) is now set to 200 autosomal common variants. However, it is unclear how genetic knowledge be clinically used in the differential diagnosis between MS and other inflammatory conditions like adult-onset postinfectious neurological syndromes (PINS). The aim of this study was to investigate whether PINS and MS have a shared genetic background using an updated polygenic risk scores. Methods: Eighty-eight PINS patients have been consecutively recruited between 1996 and 2016 at Mondino Foundation of Pavia, diagnosed according to clinical, MRI and CSF findings and followed-up for several years. Patients were typed using Illumina array, and genotypes imputed using the 1000 Genomes Project reference panel. A weighted genetic risk score (wGRS) has been calculated based on autosomal MS risk loci derived from large-scale studies, and an HLA genetic burden (HLAGB) was also calculated on loci associated to MS. Results: PINS occurred as an episode of myelitis in 44% of patients, encephalomyelitis in 44%, and encephalitis in remaining cases, with an involvement of peripheral nervous system in 41% of patients. Mean age of onset was 50.1 years, and female:male ratio was 1.4. Patients were followed-up for a mean of 7.2 years, and at last visit 55% had a low disability grade (mRS 0–1). Disease was monophasic in 67% of patients, relapsing in 18% and chronic-progressive in 15%. The wGRS of PINS cases was comparable to 370 healthy controls, while significantly lower compared to 907 bout-onset MS (BOMS) cases (wGRS= 20.9 vs 21.2; p

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