Dataset Information

Functional variants in NFKBIE and RTKN2 involved in activation of the NF-?B 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-?B pathway, and the risk alleles of the genes were implicated in the enhancement of NF-?B activity in our analyses. These results suggest that the NF-?B pathway plays a role in pathogenesis and would be a rational target for treatment of rheumatoid arthritis.

SUBMITTER: Myouzen K

PROVIDER: S-EPMC3441678 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Myouzen Keiko K Kochi Yuta Y Okada Yukinori Y Terao Chikashi C Suzuki Akari A Ikari Katsunori K Tsunoda Tatsuhiko T Takahashi Atsushi A Kubo Michiaki M Taniguchi Atsuo A Matsuda Fumihiko F Ohmura Koichiro K Momohara Shigeki S Mimori Tsuneyo T Yamanaka Hisashi H Kamatani Naoyuki N Yamada Ryo R Nakamura Yusuke Y Yamamoto Kazuhiko K

PLoS genetics 20120913 9

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 ...[more]

PMID: 23028356

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Project description:Ubiquitin D (UBD), a member of the ubiquitin‑like modifier family, has been reported to be highly expressed in various types of cancer and its overexpression is positively associated with tumor progression. However, the role and mechanism of UBD in rheumatoid arthritis (RA) remain elusive. In the present study, the gene expression profiles of GSE55457 were downloaded from the Gene Expression Omnibus database to assess differentially expressed genes and perform functional enrichment analyses. UBD was overexpressed by lentivirus transfection. The protein level of UBD, p‑p38 and p38 in RA‑fibroblast‑like synoviocytes (FLSs) were examined by western blotting. Cell Counting Kit‑8 and flow cytometry assays were used to detect the functional changes of RA‑FLSs transfected with UBD and MAPK inhibitor SB202190. The concentrations of inflammatory factors (IL‑2, IL‑6, IL‑10 and TNF‑α) were evaluated using ELISA kits. The results revealed that UBD was overexpressed in RA tissues compared with in the healthy control tissues. Functionally, UBD significantly accelerated the viability and proliferation of RA‑FLSs, whereas it inhibited their apoptosis. Furthermore, UBD significantly promoted the secretion of inflammatory factors (IL‑2, IL‑6, IL‑10 and TNF‑α). Mechanistically, elevated UBD activated phospohorylated‑p38 in RA‑FLSs. By contrast, UBD overexpression and treatment with the p38 MAPK inhibitor SB202190 not only partially relieved the UBD‑dependent effects on cell viability and proliferation, but also reversed its inhibitory effects on cell apoptosis. Furthermore, SB202190 partially inhibited the effects of UBD overexpression on the enhanced secretion of inflammatory factors. The present study indicated that UBD may mediate the activation of p38 MAPK, thereby facilitating the proliferation of RA‑FLSs and ultimately promoting the progression of RA. Therefore, UBD may be considered a potential therapeutic target and a promising prognostic biomarker for RA.

Dataset Information

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

Publications

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

Similar Datasets

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