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

Laboratory for Autoimmune Diseases, Center for Genomic Medicine (CGM), RIKEN, Yokohama, Japan.
PLoS Genetics (Impact Factor: 7.53). 09/2012; 8(9):e1002949. DOI: 10.1371/journal.pgen.1002949
Source: PubMed


Author Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting approximately 1% of the general adult population. More than 30 susceptibility loci for RA have been identified through genome-wide association studies (GWAS), but the disease-causal variants at most loci remain unknown. Here, we performed replication studies of the candidate loci of our previous GWAS using Japanese cohorts and identified variants in NFKBIE and RTKN2 gene loci that were associated with RA. To search for causal variants in both gene regions, we first examined non-synonymous (ns)SNPs that alter amino-acid sequences. As NFKBIE and RTKN2 are known to be involved in the NF-κB pathway, we evaluated the effects of nsSNPs on NF-κB activity. Next, we screened in silico variants that may regulate gene transcription using publicly available epigenetic databases and subsequently evaluated their regulatory potential using in vitro assays. As a result, we identified multiple candidate causal variants in NFKBIE (2 nsSNPs and 1 regulatory SNP) and RTKN2 (2 regulatory SNPs), indicating that our integrated in silico and in vitro approach is useful for the identification of causal variants in the post–GWAS era.

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Available from: Shigeki Momohara
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