title: The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population.
abstract: Rheumatoid arthritis (RA) is a typical complex trait and the major cause of chronic inflammation worldwide. Although multiple genetic loci have been shown for their association with the onset of RA, they cover only a part of its genetic components and are largely ethnicity-specific. To identify novel genetic factors related to the predisposition and prognosis of RA in Japanese, we conducted a large-scale genome-wide association (GWA) study. We performed a GWA analysis by scanning the genome of 1247 RA cases and 1486 controls for 277 420 single nucleotide polymorphisms (SNPs), followed by replication analysis using two independent sample sets consisting of 1865 cases and 1623 controls, and 2303 cases and 3380 controls. We identified two SNPs, rs2075876 and rs760426, in intron of the autoimmune regulator AIRE gene at chromosome 21q22 that showed strong associations with the disease (P= 3.6 × 10(-9) and P= 4.4 × 10(-8), respectively). Rs1800250, in exon7 of AIRE, was in strong linkage disequilibrium (r(2)= 0.94) with rs2075876 and introduced an amino acid alteration (S278R) in the SAND domain of the AIRE protein. In silico analysis showed the decreased transcription of AIRE by the risk allele of rs2075876 compared with the alternative allele (P= 6.8 × 10(-5)). No correlation was observed between the rs2075876 genotype and quantitative traits reflecting the progression of RA. As AIRE is a key molecule which regulates the expression and presentation of self-antigens in thymic negative selection, its downregulation by genetic polymorphisms may result in the survival of auto-reactive T cells to trigger auto-inflammation in RA.
authors.affiliation: Center for Genomic Medicine, Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.forename: Meiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Inga
authors.initials: I
authors.lastname: Melchers
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
mesh_terms: D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D014157:Transcription Factors; D000096927:AIRE Protein