title: Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis--a genome-wide study combined with immunological analyses.
abstract: Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p<0.005 in the first two collections and p<10(-4) by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP) at chromosome 18q23 showed strong association with RA (p = 2.7×10(-8), OR 1.23, 95% CI: 1.14-1.32). The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001). We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001) and patients with other connective tissue disorders (p<0.001). ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.forename: Masaki
authors.initials: M
authors.lastname: Katayama
authors.forename: Meiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Miki
authors.initials: M
authors.lastname: Kokubo
authors.forename: Gora
authors.initials: G
authors.lastname: Diop
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Toda
authors.forename: Natsuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Reiko
authors.initials: R
authors.lastname: Shinkura
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shimizu
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.forename: Inga
authors.initials: I
authors.lastname: Melchers
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Manabe
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
mesh_terms: D000906:Antibodies / Q000097:blood / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D008297:Male; D004676:Myelin Basic Protein / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D013583:Synovial Membrane / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000906:Antibodies; D004676:Myelin Basic Protein