Genetic variation in the nuclear factor kappa B pathway in relation to susceptibility to rheumatoid arthritis
ANNALS OF THE RHEUMATIC DISEASES
Authors: Dieguez-Gonzalez, R.; Akar, S.; Calaza, M.; Perez-Pampin, E.; Costas, J.; Torres, M.; Vicario, J. L.; Velloso, M. L.; Navarro, F.; Narvaez, J.; Joven, B.; Herrero-Beaumont, G.; Gonzalez-Alvaro, I.; Fernandez-Gutierrez, B.; de la Serna, A. R.; Carreno, L.; Lopez-Longo, J.; Caliz, R.; Collado-Escobar, M. D.; Blanco, F. J.; Fernandez-Lopez, C.; Balsa, A.; Pascual-Salcedo, D.; Gomez-Reino, J. J.; Gonzalez, A.
Abstract
Objective: To examine genetic association between rheumatoid arthritis (RA) and known polymorphisms in core genes of the nuclear factor (NF)kappa B pathway, the major intracellular pathway in RA pathogenesis. Methods: Discovery and replication sample sets of Spanish patients with RA and controls were studied. A total of 181 single nucleotide polymorphisms ( SNPs) uniformly spaced along the genomic sequences of 17 core genes of the NFkB pathway (REL, RELA, RELB, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBIE, IKBKA, IKBKB, IKBKE, IKBKAP, KBRAS1, KBRAS2, MAP3K1, MAP3K14, TAX1BP1) were studied by mass spectrometry analysis complemented with 5'-nuclease fluorescence assays in the discovery set, 458 patients with RA and 657 controls. SNPs showing nominal significant differences were further investigated in the replication set of 1189 patients with RA and 1092 controls. Results: No clear reproducible association was found, although 12 SNPs in IKBKB, IKBKE and REL genes showed significant association in the discovery set. Interestingly, two of the SNPs in the IKBKE gene, weakly associated in the discovery phase, showed a trend to significant association in the replication phase. Pooling both sample sets together, the association with these two SNPs was significant. Conclusion: We did not find any major effect among the explored members of the NF-kappa B pathway in RA susceptibility. However, it is possible that variation in the IKBKE gene could have a small effect that requires replication in additional studies.
Epstein-Barr virus latent membrane protein (LMP1) induces specific NF kappa B complexes in human T-lymphoid cells
VIRUS RESEARCH
Authors: Chien, ML; Hammarskjold, ML
Abstract
The Epstein-Barr virus (EBV) latent membrane protein (LMP1) is believed to play a crucial role in oncogenesis mediated by this virus. We and others previously showed that LMP1 can induce NF kappa B activity in several non-lymphoid cells and B-lymphoid cell lines. Here we show that LMP1 is also able to efficiently induce NF kappa B in human T-lymphoid and monocytic cells. Specific NF kappa B complexes were detected in the nuclei of transfected Jurkat cells using gel mobility shift assays and Western blot analyses; Using antibodies, we demonstrated that these complexes contain NF kappa B subunits NFkB1, NFkB2, RelA and c-Rel. Our results also showed that the NF kappa B complexes induced by LMP1 are able to bind to the NF kappa B consensus sequence in the promoter of the interleukin-2 alpha receptor gene and induce expression from a minimal promoter linked to four tandem copies of this sequence. This suggests a possible mechanism by which LMP1 could induce T-cell activation and proliferation. (C) 2000 Elsevier Science B.V. All rights reserved.