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Recent investigations into the nuclear factor kappaB (NFκB) pathway have included analyses of common variation in NFKBIB (HGNC:7798) in cohorts of patients with rheumatoid arthritis (RA) (MONDO_0008383). Although multiple large‐scale candidate gene and genome‑wide studies have evaluated key NFκB regulators, the data for NFKBIB have not met conventional thresholds for a robust disease association. In one multi‐patient study of RA that surveyed 17 core NFκB pathway genes, no clear reproducible association with RA susceptibility was identified (PMID:18434448).
Despite the overall negative findings for direct disease susceptibility, subsequent pharmacogenomic meta‑analyses have provided modest evidence that common variants in NFKBIB may influence the response to anti‑tumor necrosis factor (anti‑TNF) therapy. One systematic review and meta‑analysis, which included data from several hundred patients, noted that while multiple SNPs in NFκB pathway genes were examined, the effect sizes for NFKBIB variants were small, reaching nominal significance only in combined analyses (PMID:28607508).
Another study focused on markers predicting anti‑TNF treatment response reported that although NFKBIB was among several genes evaluated, the signal for NFKBIB was less compelling than for other candidates; meta‑analyses incorporating this gene revealed only a minor contribution to the overall pharmacogenetic profile (PMID:27698401).
Notably, although several single nucleotide polymorphisms (e.g. rs3136645 and rs9403) have been interrogated, no definitive HGVS‑coded variant (i.e. one beginning with “c.” and including a standardized protein change) has emerged for NFKBIB. This absence of a clearly pathogenic coding allele reinforces the limited strength of the genetic evidence.
Functional studies within NFκB signaling models have suggested that alterations in NFKBIB expression or function could subtly modulate NFκB activity; however, such experimental findings remain preliminary. There is currently insufficient functional evidence from animal or cellular rescue experiments to definitively link NFKBIB disruption with the RA phenotype.
In summary, while genetic investigations and limited functional assessments hint at a modulatory role for NFKBIB in influencing anti‑TNF treatment response in RA, the overall evidence remains limited due to modest effect sizes, a lack of robust replication, and the absence of definitive causal variants. Key take‑home: current findings advise caution in using NFKBIB as a standalone diagnostic biomarker but encourage further integrative studies to potentially refine its clinical utility in RA management.
Gene–Disease AssociationLimitedLarge‑scale candidate gene studies and genome‑wide analyses have failed to demonstrate a robust association between NFKBIB and rheumatoid arthritis; nominal associations in meta‑analyses and treatment response studies indicate only a modest effect (PMID:18434448, PMID:28607508). Genetic EvidenceLimitedData from multiple cohorts, including both discovery and replication phases comprising over 400 RA patients, indicate weak and non‐reproducible effects for NFKBIB variants. Common SNPs such as rs3136645 have been evaluated; however, the absence of a definitive HGVS‑coded variant limits the strength of the genetic evidence. Functional EvidenceLimitedPreliminary functional assays in NFκB signaling models have suggested potential perturbations related to NFKBIB; however, reproducible experimental validation in disease‐relevant models has not been achieved. |