Page 38 - GPD-4-3

Gene & Protein in Disease TNFA polymorphism and risk of endometriosis

TNFA expression; for instance, the c.-238 G>A variant in endometriosis. 38-41 These studies highlight the critical
demonstrates a modest impact on TNFA promoter activity, role of TNF-α in inflammatory responses, immune
possibly due to changes in deoxyribonucleic acid curvature. function, and cellular processes, all of which are key
Deoxyribonucleic acid bending, whether intrinsic (due contributors to the pathogenesis of endometriosis.
to the presence of other alleles) or induced by activator Evidence from the Kyoto Encyclopedia of Genes and
proteins, is known to influence gene expression and TNFA Genomes pathway database indicates that the activation
promoter activity, ultimately affecting gene expression. of TNF-α signaling is essential in triggering nuclear factor
6
Several studies have reported significant differences in kappa-light-chain-enhancer of activated B cells (NF-κB)
TNF-α levels in both serum and peritoneal fluid. transcription factors. This activation initiates a cascade of
7-9
10
Specifically, elevated TNFA concentrations have been intracellular signaling pathways that regulate the expression
observed in both serum and peritoneal fluid during the of genes involved in inflammation, immune responses,
early stages of the disease, with a marked reduction in and cellular survival, all of which are highly relevant to the
levels as the condition progresses in severity. Furthermore, pathogenesis of endometriosis (Figure 5). Both in vivo
7
42
elevated levels of soluble TNF receptor I have been and in vitro studies have consistently shown that NF-κB-
associated with endometriosis, especially in its early mediated gene transcription contributes to inflammation,
stages. 18,32 Hence, it has been hypothesized that variations invasion, angiogenesis (the formation of blood vessels),
in the TNFA gene may influence the risk of developing and cell division, while also preventing apoptosis in
endometriosis. However, studies exploring this hypothesis endometrial cells. 4,5,43 Zdrojkowski and colleagues have
44
across various population groups have yielded conflicting extensively elucidated the impact of TNF-α in the context
results (Table 3). Therefore, the present meta-analysis aims of endometriosis. They explained how the release of pro-
to clarify the relationship between the TNFA variants and fibrotic cytokines, such as TNF-α, triggers immune cell
endometriosis risk while ensuring an adequate sample size infiltration and activates the NF-κB signaling pathway,
for reliable conclusions. ultimately leading to fibrogenesis. Furthermore, they
In this study, a systematic review of multiple studies highlighted that as the disease progresses, dysregulated
on TNFA variants and their potential association with immune cells continue to produce pro-fibrotic cytokines,
endometriosis was conducted, following the PRISMA further influencing extracellular matrix remodeling
guidelines. Our analysis, encompassing variants such through NF-κB pathways. Their research indicates
as -238 G>A, -308 G>A, -857 C>T, -863 C>A, and -1031 that elevated NF-κB activity is closely associated with
T>C, revealed no significant associations across various alterations in cytokine release and hyaluronan synthase
genetic models (Table 5), verifying the results of previous activity, both of which contribute to the development of
meta-analyses, 33,34 but contrasting with other studies. 35,36 endometriosis. In addition, studies suggest that a TNF-α
44
These discrepancies may stem from differences in the inhibitor could mitigate the harmful effects observed in
number of studies included in each meta-analysis. the peritoneal fluid of women with endometriosis. This
A notable strength of the present meta-analysis is the use fluid slows embryo development and increases cell death
of the Bonferroni correction for multiple comparisons, compared to fluid from women without the condition.
which reduced the risk of Type I errors (false positives) Elevated TNF-α levels were found in the affected fluid, and
by adjusting the significance threshold for each test. blocking TNF-α reversed these effects, offering potential
However, this correction also increases the potential for therapeutic benefits for treating endometriosis-related
Type II errors (false negatives), as the criteria for statistical infertility. 45
significance become more stringent. 37 One strength of our meta-analysis is that it was conducted
Despite the lack of a significant association between in accordance with the PRISMA guidelines, thereby
the upstream variants we studied and the risk of providing a standardized and transparent framework for
endometriosis, it would be inaccurate to conclusively rule conducting meta-analyses. A comprehensive literature
out TNFA as a potential risk factor based solely on these search was undertaken, utilizing various scholarly
variants. Our study focused on specific genetic variants, databases to substantiate the findings of the study. The
which may not fully capture the complexity of the TNF processes of data extraction and quality assessment
pathway or its role in endometriosis. In addition, factors were carried out with meticulous attention, aided by the
such as gene expression and environmental influences contributions of our authors. The quality of each included
were not considered, yet they may also play crucial roles in study was appraised using the NOS, ensuring a consistent
the disease’s development. As previously noted, substantial and reliable methodological approach. In our statistical
evidence supports the involvement of the TNF-α pathway analysis, we employed the Bonferroni correction to address

Volume 4 Issue 3 (2025) 12 doi: 10.36922/gpd.5204