title: Functional variants in NFKBIE and RTKN2 involved in activation of the NF-κB pathway are associated with rheumatoid arthritis in Japanese.
abstract: Rheumatoid arthritis is an autoimmune disease with a complex etiology, leading to inflammation of synovial tissue and joint destruction. Through a genome-wide association study (GWAS) and two replication studies in the Japanese population (7,907 cases and 35,362 controls), we identified two gene loci associated with rheumatoid arthritis susceptibility (NFKBIE at 6p21.1, rs2233434, odds ratio (OR) = 1.20, P = 1.3 × 10(-15); RTKN2 at 10q21.2, rs3125734, OR = 1.20, P = 4.6 × 10(-9)). In addition to two functional non-synonymous SNPs in NFKBIE, we identified candidate causal SNPs with regulatory potential in NFKBIE and RTKN2 gene regions by integrating in silico analysis using public genome databases and subsequent in vitro analysis. Both of these genes are known to regulate the NF-κB pathway, and the risk alleles of the genes were implicated in the enhancement of NF-κB activity in our analyses. These results suggest that the NF-κB pathway plays a role in pathogenesis and would be a rational target for treatment of rheumatoid arthritis.
authors.affiliation: Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Myouzen
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikari
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Atsuo
authors.initials: A
authors.lastname: Taniguchi
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.forename: Shigeki
authors.initials: S
authors.lastname: Momohara
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007564:Japan; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C105627:NFKBIE protein, human; D011518:Proto-Oncogene Proteins; C495970:RTKN2 protein, human