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Gene & Protein in Disease TNFA polymorphism and risk of endometriosis

Figure 5. Activation of tumor necrosis factor-alpha (TNF-α) receptors and the downstream signaling cascade leading to the activation of nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-κB). TNF-α binds to the extracellular domain of tumor necrosis factor receptor 1 (TNF-R1), which
triggers receptor trimerization and the recruitment of the adaptor protein tumor necrosis factor receptor type 1-associated death domain protein (TRADD).
TRADD interacts with receptor-interacting protein (RIP) and tumor necrosis factor receptor-associated factor 2 (TRAF2), which, along with E3 ligases
(cellular inhibitor of apoptosis protein [cIAP] 1 and cIAP2), ubiquitinate RIP. This modification enables the recruitment and activation of transforming
growth factor-activated kinase-1 (TAK1) through TAK1-binding proteins (TAB). Activated TAK1 then phosphorylates the IκB kinase (IKK) complex,
including the regulatory subunit nuclear factor κB essential modulator (NEMO), resulting in the phosphorylation and degradation of nuclear factor of
kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), an inhibitor of NF-κB. The released NF-κB dimers translocate to the nucleus,
where they promote the transcription of genes involved in inflammation and tissue remodeling, contributing to the pathogenesis of endometriosis.
Abbreviations: A1/Bf1-1: Bcl-2-related protein A1; COX2: Cyclooxygenase-2; BCl-XL: B-cell lymphoma-extra large; Bcl-2: B-cell lymphoma 2;
c-FLIP: Cellular FLICE (FADD-like interleukin-1β-converting enzyme)-inhibitory protein; DNA: Deoxyribonucleic acid; gadd45B: Growth arrest and
DNA-damage-inducible beta; IKK-A: Inhibitor of nuclear factor-κB kinase alpha; IKK-B: Inhibitor of nuclear factor-κB kinase beta; IL-1B: Interleukin-1
beta; MIP-1B: Macrophage inflammatory protein 1 beta; MIP-2: Macrophage inflammatory protein 2; p50: p50 protein precursor; p65: Transcription
factor p65; TNF-R1: Tumor necrosis factor receptor 1; TRAF: Tumor necrosis factor receptor-associated factor; VCAM-1: Vascular cell adhesion protein
1; XIAP: X-linked inhibitor of apoptosis protein.

the issue of multiple comparisons, effectively reducing the from HWE were observed in certain studies, suggesting
likelihood of false-positive results. In addition, we utilized potential genotyping errors. In addition, we included only
TSA to determine the necessary sample size, providing a English-language articles, which may have introduced
robust statistical mechanism to ensure the adequacy of our language bias. Heterogeneity remains a significant
sample. concern in meta-analysis, as it can influence the overall
However, there are several limitations to our meta- results. The sample size was also found to be inadequate,
analysis. It included only peer-reviewed articles, which as demonstrated by the TSA results (Figures S1-S5).
may have introduced publication bias. Some studies lacked Moreover, the present meta-analysis did not investigate
genotypic data and were therefore excluded. Deviations gene-gene or gene-environment interactions, despite the

Volume 4 Issue 3 (2025) 13 doi: 10.36922/gpd.5204