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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Article numbere1002949
JournalPLoS Genetics
Volume8
Issue number9
DOIs
Publication statusPublished - 01-09-2012

Fingerprint

rheumatoid arthritis
Rheumatoid Arthritis
gene
odds ratio
Genes
Single Nucleotide Polymorphism
genes
genome
Odds Ratio
autoimmune diseases
Genome-Wide Association Study
etiology
Computer Simulation
Autoimmune Diseases
allele
pathogenesis
Joints
inflammation
Alleles
Genome

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Myouzen, Keiko ; Kochi, Yuta ; Okada, Yukinori ; Terao, Chikashi ; Suzuki, Akari ; Ikari, Katsunori ; Tsunoda, Tatsuhiko ; Takahashi, Atsushi ; Kubo, Michiaki ; Taniguchi, Atsuo ; Matsuda, Fumihiko ; Ohmura, Koichiro ; Momohara, Shigeki ; Mimori, Tsuneyo ; Yamanaka, Hisashi ; Kamatani, Naoyuki ; Yamada, Ryo ; Nakamura, Yusuke ; Yamamoto, Kazuhiko. / Functional Variants in NFKBIE and RTKN2 Involved in Activation of the NF-κB Pathway Are Associated with Rheumatoid Arthritis in Japanese. In: PLoS Genetics. 2012 ; Vol. 8, No. 9.
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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.",
author = "Keiko Myouzen and Yuta Kochi and Yukinori Okada and Chikashi Terao and Akari Suzuki and Katsunori Ikari and Tatsuhiko Tsunoda and Atsushi Takahashi and Michiaki Kubo and Atsuo Taniguchi and Fumihiko Matsuda and Koichiro Ohmura and Shigeki Momohara and Tsuneyo Mimori and Hisashi Yamanaka and Naoyuki Kamatani and Ryo Yamada and Yusuke Nakamura and Kazuhiko Yamamoto",
year = "2012",
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Myouzen, K, Kochi, Y, Okada, Y, Terao, C, Suzuki, A, Ikari, K, Tsunoda, T, Takahashi, A, Kubo, M, Taniguchi, A, Matsuda, F, Ohmura, K, Momohara, S, Mimori, T, Yamanaka, H, Kamatani, N, Yamada, R, Nakamura, Y & Yamamoto, K 2012, 'Functional Variants in NFKBIE and RTKN2 Involved in Activation of the NF-κB Pathway Are Associated with Rheumatoid Arthritis in Japanese', PLoS Genetics, vol. 8, no. 9, e1002949. https://doi.org/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. / Myouzen, Keiko; Kochi, Yuta; Okada, Yukinori; Terao, Chikashi; Suzuki, Akari; Ikari, Katsunori; Tsunoda, Tatsuhiko; Takahashi, Atsushi; Kubo, Michiaki; Taniguchi, Atsuo; Matsuda, Fumihiko; Ohmura, Koichiro; Momohara, Shigeki; Mimori, Tsuneyo; Yamanaka, Hisashi; Kamatani, Naoyuki; Yamada, Ryo; Nakamura, Yusuke; Yamamoto, Kazuhiko.

In: PLoS Genetics, Vol. 8, No. 9, e1002949, 01.09.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Functional Variants in NFKBIE and RTKN2 Involved in Activation of the NF-κB Pathway Are Associated with Rheumatoid Arthritis in Japanese

AU - Myouzen, Keiko

AU - Kochi, Yuta

AU - Okada, Yukinori

AU - Terao, Chikashi

AU - Suzuki, Akari

AU - Ikari, Katsunori

AU - Tsunoda, Tatsuhiko

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Taniguchi, Atsuo

AU - Matsuda, Fumihiko

AU - Ohmura, Koichiro

AU - Momohara, Shigeki

AU - Mimori, Tsuneyo

AU - Yamanaka, Hisashi

AU - Kamatani, Naoyuki

AU - Yamada, Ryo

AU - Nakamura, Yusuke

AU - Yamamoto, Kazuhiko

PY - 2012/9/1

Y1 - 2012/9/1

N2 - 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.

AB - 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.

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