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.
Activation of the transcription factor, nuclear factor kappa-B, during the estrous cycle and early pregnancy in the pig
REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY
Authors: Ross, Jason W.; Ashworth, Morgan D.; Mathew, Daniel; Reagan, Patrick; Ritchey, Jerry W.; Hayashi, Kanako; Spencer, Thomas E.; Lucy, Matthew; Geisert, Rodney D.
Abstract
Establishment and maintenance of pregnancy in the pig involves intricate communication between the developing conceptuses and the maternal endometrium. This process occurs during trophoblast elongation which is spaciotemporally associated with conceptus synthesis and release of IL1B concomitant with pregnancy-specific endometrial up-regulation of IL-1 receptors, providing the potential for activation of the transcription factor, NFKB. The objective of the current investigation was to determine changes in expression and cellular localization of NFKB and associated factors during the estrous cycle and early pregnancy in the pig. In situ hybridization was used to localize changes in PGR, ESR1, and TNFRSF11A during the peri-implantation period. Quantitative RT-PCR was utilized to demonstrate gene expression changes for NFKB1, RELA, TNFRSF11A, TLR4, NFKBIA and NFKBIB. Transcription factor ELISA demonstrated an overall increase in RELA during the peri-implantation period in both cyclic and pregnant gilts. While the presence of TNFSF11A and TLR4 were both detected, TLR4 expression changes were temporally associated with NFKB expression and activation. Collectively, these data demonstrate that NFKB activation may occur during the period of uterine receptivity in both the cyclic and pregnant endometrium.