Functional variants in NFKBIE and RTKN2 involved in activation of the NF-κB pathway are associated with rheumatoid arthritis in Japanese

Keiko Myouzen; Yuta Kochi; Yukinori Okada; Chikashi Terao; Akari Suzuki; Katsunori Ikari; Tatsuhiko Tsunoda; Atsushi Takahashi; Michiaki Kubo; Atsuo Taniguchi; Fumihiko Matsuda; Koichiro Ohmura; Shigeki Momohara; Tsuneyo Mimori; Hisashi Yamanaka; Naoyuki Kamatani; Ryo Yamada; Yusuke Nakamura; Kazuhiko Yamamoto

doi:10.1371/journal.pgen.1002949

Functional variants in NFKBIE and RTKN2 involved in activation of the NF-κB pathway are associated with rheumatoid arthritis in Japanese

PLoS Genet. 2012 Sep;8(9):e1002949. doi: 10.1371/journal.pgen.1002949. Epub 2012 Sep 13.

Affiliation

¹ Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arthritis, Rheumatoid* / genetics
Arthritis, Rheumatoid* / metabolism
Arthritis, Rheumatoid* / pathology
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
I-kappa B Proteins* / genetics
I-kappa B Proteins* / metabolism
Intracellular Signaling Peptides and Proteins* / genetics
Intracellular Signaling Peptides and Proteins* / metabolism
Japan
NF-kappa B / metabolism
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins* / genetics
Proto-Oncogene Proteins* / metabolism
Signal Transduction

Substances

I-kappa B Proteins
Intracellular Signaling Peptides and Proteins
NF-kappa B
NFKBIE protein, human
Proto-Oncogene Proteins
RTKN2 protein, human

Grants and funding

This work was conducted as a part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Sciences, and Technology of the Japanese government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.