title: A functional variant in ERAP1 predisposes to multiple sclerosis.
abstract: The ERAP1 gene encodes an aminopeptidase involved in antigen processing. A functional polymorphism in the gene (rs30187, Arg528Lys) associates with susceptibility to ankylosying spondylitis (AS), whereas a SNP in the interacting ERAP2 gene increases susceptibility to another inflammatory autoimmune disorder, Crohn's disease (CD). We analysed rs30187 in 572 Italian patients with CD and in 517 subjects suffering from multiple sclerosis (MS); for each cohort, an independent sex- and age-matched control group was genotyped. The frequency of the 528Arg allele was significantly higher in both disease cohorts compared to the respective control population (for CD, OR = 1.20 95%CI: 1.01-1.43, p = 0.036; for RRMS, OR = 1.26; 95%CI: 1.04-1.51, p = 0.01). Meta-analysis with the Wellcome Trust Cases Control Consortium GWAS data confirmed the association with MS (p(meta) = 0.005), but not with CD. In AS, the rs30187 variant has a predisposing effect only in an HLA-B27 allelic background. It remains to be evaluated whether interaction between ERAP1 and distinct HLA class I alleles also affects the predisposition to MS, and explains the failure to provide definitive evidence for a role of rs30187 in CD. Results herein support the emerging concept that a subset of master-regulatory genes underlay the pathogenesis of autoimmunity.
authors.affiliation: Don C. Gnocchi Foundation ONLUS, Milano, Italy. fguerini@dongnocchi
authors.forename: Franca Rosa
authors.initials: FR
authors.lastname: Guerini
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.forename: Cristina
authors.initials: C
authors.lastname: Agliardi
authors.forename: Domenico
authors.initials: D
authors.lastname: Caputo
authors.forename: Andrea
authors.initials: A
authors.lastname: Cassinotti
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000328:Adult; D000626:Aminopeptidases / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D015778:Minor Histocompatibility Antigens; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human