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John, G. ; Hegarty, J.P.* ; Yu, W.* ; Berg, A.* ; Pastor, D.M.* ; Kelly, A.A.* ; Wang, Y.* ; Poritz, L.S.* ; Schreiber, S.* ; Koltun, W.A.* ; Lin, Z.*

NKX2-3 variant rs11190140 is associated with IBD and alters binding of NFAT.

Mol. Genet. Metab. 104, 174-179 (2011)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
NKX2-3 SNP rs11190140 is associated with inflammatory bowel disease (IBD). The T allele is over-transmitted in IBD and the C allele represents a potential CpG methylation site. We hypothesize that genetic variation and/or methylation of SNP rs11190140 may play a role in NKX2-3 gene expression by affecting transcription factor binding. We studied 233 IBD cases and 250 unrelated healthy individuals from an IBD population from central Pennsylvania and performed genotype analyses of the genetic variation and methylation status analysis using PCR-based RFLP. For transcription factor binding, nuclear extracts from human B cells were incubated with biotin-labeled oligonucleotide sequences of the NKX2-3 promoter region containing the genetic variation of T, non-methylated C or methylated C at rs11190140, followed by biotin pull-down and Western blot analysis for transcription factors SP1, NFAT1, NF-κB, and ETS-1. In case-control analysis, the genetic variation was significantly associated with IBD (OR=0.503, 95% CI=0.330-0.764, p<0.001). Methylation status analyses revealed that the C allele is subject to modification by DNA methylation. transcription factor binding assay indicated distinct differential binding of NFAT1 to the NKX2-3 promoter sequence, with higher binding to those with non-methylated and methylated C than to T. The binding of NFAT1 to the NKX2-3 promoter region with rs1190140 was confirmed by ChIP assay. We speculate that the rs11190140 may regulate NKX2-3 expression and have a role in IBD pathogenesis.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords NKX2-3; IBD; Genetic association; DNA methylation; NFAT; Transcription factor binding
ISSN (print) / ISBN 1096-7192
e-ISSN 1096-7192
Journal Molecular Genetics and Metabolism
Quellenangaben Volume: 104, Issue: 1-2, Pages: 174-179 Article Number: , Supplement: ,
Publisher Elsevier
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Lung Biology (LHI)