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.

Download full-text


Available from: Shigeki Momohara, Oct 07, 2015
29 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Systemic lupus erythematosus is a complex autoimmune disease affecting multiple organ systems. Currently, diagnosis relies upon meeting at least four out of eleven criteria outlined by the ACR. The scientific community actively pursues discovery of novel diagnostics in the hope of better identifying susceptible individuals in early stages of disease. Comprehensive studies have been conducted at multiple biological levels including: DNA (or genomics), mRNA (or transcriptomics), protein (or proteomics) and metabolites (or metabolomics). The 'omics' platforms allow us to re-examine systemic lupus erythematosus at a greater degree of molecular resolution. More importantly, one is hopeful that these 'omics' platforms may yield newer biomarkers for systemic lupus erythematosus that can help clinicians track the disease course with greater sensitivity and specificity.
    International Journal of Clinical Rheumatology 12/2013; 8(6):671-687. DOI:10.2217/ijr.13.59
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: NF-kB. NF-kB має еволюційне значення не тільки для імунної системи, але й для інших органів і систем, визначаючи на експресію генів, які регулюють виживання, диференціювання і проліферацію клітин. Сигнали NF-kB, опосередковані NEMO-залежними або NEMO-незалежними IKK комплексами, слід розглядати в контексті єдиної регулюючої або сигналізуючої системи. В даному огляді ми відстежуємо деякі з важливих відкриттів, що супроводжують опис єдиної системи IKK-IKB-NF-kB для канонічної і неканонічної сигналізації. Зокрема, ми описуємо мінливість генів цієї системи та її фенотипні наслідки. Генетичні порушення цієї системи призводили до змін органогенезу і регенерації, до злоякісних пухлин, аутоімунних і запальних захворювань. Всі члени IKK-IKB-NF-kB системи можуть стати предметом як дослідження, так і маніпуляції генами. Системний генетичний підхід може стати потужним інструментом для дослідження функцій системи IKK-IKB-NF-kB і для відкриття нових діагностичних і терапевтичних стратегій. Ключові слова: NF-kB, поліморфізми, мутація, захворювання, запалення, злоякісне новоутворення * To cite this English version: Kaidashev I. P. IKK-IKB-NF-KB gene manipulations and polymorphisms in relation to susceptibility to different diseases / / Problemy ekologii ta medytsyny.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background The transcription factor nuclear factor-kappa B (NF-κB) acts as a central regulator of immune response, stress response, cell proliferation, and apoptosis. Aberrant regulation of NF-κB function triggers development of cancers, metabolic diseases, and autoimmune diseases. We attempted to characterize a global picture of the NF-κB target gene network relevant to the immunopathogenesis of multiple sclerosis (MS). Methods We identified the comprehensive set of 918 NF-κB p65 binding sites on protein-coding genes from chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset of TNFα-stimulated human B lymphoblastoid cells. The molecular network was studied by a battery of pathway analysis tools of bioinformatics. Results The GenomeJack genome viewer showed that NF-κB p65 binding sites were accumulated in promoter (35.5%) and intronic (54.9%) regions with an existence of the NF-κB consensus sequence motif. A set of 52 genes (5.7%) corresponded to known NF-κB targets by database search. KEGG, PANTHER, and Ingenuity Pathways Analysis (IPA) revealed that the NF-κB p65 target gene network is linked to regulation of immune functions and oncogenesis, including B cell receptor signaling, T cell activation pathway, Toll-like receptor signaling, and apoptosis signaling, and molecular mechanisms of cancers. KeyMolnet indicated an involvement of the complex crosstalk among core transcription factors in the NF-κB p65 target gene network. Furthermore, the set of NF-κB p65 target genes included 10 genes among 98 MS risk alleles and 49 molecules among 709 MS brain lesion-specific proteins. Conclusions These results suggest that aberrant regulation of NF-κB-mediated gene expression, by inducing dysfunction of diverse immune functions, is closely associated with development and progression of MS.
    Multiple Sclerosis and Related Disorders 01/2014; 3(1):94–106. DOI:10.1016/j.msard.2013.04.005 · 0.88 Impact Factor
Show more