Evaluation of genetic polymorphisms in TNF‑α‑308G/A rs1800629 associated with susceptibility and severity of rheumatoid arthritis: A systematic review and meta‑analysis
- Authors:
- Published online on: May 13, 2024 https://doi.org/10.3892/etm.2024.12567
- Article Number: 279
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Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Rheumatoid arthritis (RA) is a common, chronic autoimmune joint disease characterized by synovial inflammation, pannus formation and joint damage as major pathological features. The global incidence of RA is 0.5-1% (1). RA is characterized by chronic systemic inflammation, which mainly affects the joint synovial tissue, eventually leading to joint destruction, functional disability and even death, severely affecting the quality of life of patients (2). The etiology and pathogenesis of RA remain largely unknown. Currently, it is considered by most scholars that this is the result of the combined effects of genetics, environment, infection and other factors, leading to an imbalance in immune regulation and the induction of a series of joint tissue inflammations (3). It has been hypothesized that TNF-α-308G/A rs1800629 is closely related to the pathogenesis and severity of RA (4,5), while other studies consider that there is no relationship between the two (6,7). Different studies produced different results (4-7), which may be related to the sample size, quality and whether the frequency of the control genotype conformed to the Hardy-Weinberg equilibrium (HWE) (8). Therefore, the current meta-analysis of the two aspects of susceptibility and severity of TNF-α-308G/A rs1800629 and RA was conducted to obtain reliable theoretical support and research results and provide evidence-based medical evidence for in-depth research on genetic susceptibility.
Materials and methods
Search policy
The PubMed (https://pubmed.ncbi.nlm.nih.gov), EMBASE (https://www.embase.com), Web of Science (https://www.webofscience.com/wos) and CNKI (https://www.cnki.net/) databases were employed. The key words searched were: ‘rheumatoid arthritis’, ‘TNF-α’ and ‘polymorphism’. The search strategy was as follows: (polymorphism or variant or variation or mutation or SNP or genome-wide association study or genetic association study or genotype or allele) AND (rheumatoid arthritis) OR (RA) AND (Tumor Necrosis Factor-alpha) OR (Tumor Necrosis Factor alpha) OR (Cachectin) OR (Cachectin-Tumor Necrosis Factor) OR (Tumor Necrosis Factor Ligand Superfamily Member 2) OR (Tumor Necrosis Factor) OR (TNFalpha) OR (TNF-alpha) OR (TNF-α). The search period ranged from the establishment of each database until May 2023.
Inclusion and exclusion criteria
The inclusion criteria were as follows: i) The study participants were patients with RA, and there were clear diagnostic criteria; ii) the type of study was a case-control study or a cohort study; iii) the research content was the relationship between TNF-α-308G/A rs1800629 gene polymorphisms and the susceptibility or severity of RA; iv) the study included complete genotype and allele frequency data and inclusion or availability to calculate odds ratio (OR) and 95% confidence intervals (CI); v) the control group conformed to HWE.
The exclusion criteria were as follows: i) Duplicate publications; ii) no health control studies; iii) studies with incomplete data or an inability to calculate OR and 95% CI; and iv) animal experimental literature.
Data extraction
Two authors independently screened and extracted the data; in cases of disagreement, a third author decided. Missing data were supplemented as much as possible by contacting the authors of the studies. The data extracted included: i) First author and year of publication; ii) country, geographic region, sex composition, mean age and diagnostic criteria of the study subjects; iii) sample size, allele and genotype frequency of the RA and control groups; and iv) whether they conformed to the HWE.
Literature quality evaluation criteria
The Newcastle-Ottawa Scale (NOS) evaluated the quality of the literature. The NOS scale includes three dimensions with a total of eight items: Four items for study object selection, one item for intergroup comparability and three items for outcome measurement. In addition to the comparability item, the highest score was two points, and the other items could reach up to one point, with a score range of 0 to 9 points. The higher the overall score, the higher the quality of the study. The NOS score is divided into three grades: Low, medium and high quality, namely <5 points, 5-7 points and ≥8 points (9).
Statistical methods
The present study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (10). The meta-analysis was performed using Stata 17.0 (StataCorp LP). Using OR and its 95% CI to assess the strength of the association between TNF-α-308G/A rs1800629 gene polymorphisms and the risk and severity of RA, P<0.05 was considered statistically significant. Heterogeneity was assessed using Cochrane's Q test and I2 values, and pooled analyses were performed using a random-effects model when I2≤50% between study groups. When heterogeneity could not be completely eliminated, a random-effects model was also used. The following five genetic models were used for comparison: Allele, dominant, recessive, co-dominant and super-dominant models. Subgroup analysis was carried out for further research. The subgroups were divided into: Asian, South American, European, North American and African groups according to the source of the patient. Sensitivity analyses were conducted by excluding literature on a case-by-case basis to observe the effect of each study on the overall effect size or by using Stata 17.0 to assess the robustness of the results. Funnel plots were only used to visualize publication bias for the number of included studies ≥10. Publication bias was detected using Egger's test, and no publication bias was considered when P>0.05(11).
Results
Search results
According to the search strategy, 1,862 relevant studies were retrieved from the databases, duplicate publications were removed, and 34 studies were screened in combination with the aforementioned inclusion and exclusion criteria. The study of TNF-α-308G/A rs1800629 gene polymorphisms and susceptibility to RA included 6,030 cases in the RA group and 6,581 cases in the control group. TNF-α-308G/A rs1800629 gene polymorphisms and the severity of RA included 483 cases in the RA group and 545 cases in the control group. The selection process and results of the included studies are demonstrated in Fig. 1.
Basic information included in the literature
The basic characteristics of the included studies and the NOS score results are presented in Table I. The specific sample size, genotype and allele frequency included in the study of TNF-α-308G/A rs1800629 polymorphisms and susceptibility to RA are shown in Table II. Of the studies included in the meta-analysis, 16 were conducted in the Asian population, four in the South American population, 10 in the European population, three in the North American population and one in the African population. The specific sample size, genotype and allele frequency included in the study of TNF-α-308G/A rs1800629 polymorphisms and the severity of RA are presented in Table III. Of the studies included in the meta-analysis, one was conducted in North Americans, three in Asians and two in Europeans.
 | Table IISample size, genotype and allele frequency in rheumatoid arthritis and control groups in susceptibility studies. |
Results of the meta-analysis. TNF-α-308G/A rs1800629 polymorphisms and susceptibility to RA
A total of 34 studies were included in the present analysis. Significant study heterogeneity was observed in allele, dominant and super-dominant models (I2≥50%, P<0.05); therefore, random-effect models were used for analysis. Other genetic models were less heterogeneous and were also analyzed using random-effect models (I2<50%, P>0.05). No significant association between TNF-α-308G/A rs1800629 gene polymorphisms and susceptibility to RA was observed in the five gene models (P>0.05). After subgroup analysis, no clear association was observed among the different geographic regions. Detailed data is listed in Table IV.
| Table IVSummary of associations between TNF-α-308G/A rs1800629 gene polymorphisms and rheumatoid arthritis. |
TNF-α-308G/A rs1800629 polymorphisms and severity of RA. A total of six studies were included in the meta-analysis. Significant study heterogeneity was observed in allele models, dominant gene models and super-dominant models (I2≥50%, P<0.05); therefore, random-effect models were used for analysis. Recessive and co-dominant models were also analyzed using random-effect models. In the overall calculation, TNF-α-308G/A rs1800629 polymorphisms were not statistically significantly associated with the severity of RA. After subgroup analysis by geographic region, TNF-α-308G/A rs1800629 polymorphisms were significantly associated with RA severity in European populations, GA + AA vs. GG: (OR=0.503, 95% CI: 0.297-0.853 and P=0.011); GG + AA vs. GA: (OR=2.268, 95% CI: 1.434-3.590 and P<0.001). No other models were statistically significant. Forest plots of the dominant gene models and super-dominant models are illustrated in Figs. 2 and 3, and detailed data are revealed in Table V.
| Table VSummary of associations between TNF-α-308G/A rs1800629 gene polymorphisms and rheumatoid arthritis. |
Heterogeneity and sensitivity analyses. Heterogeneity between the studies was observed in the current meta-analysis. Subgroup analyses were performed to explore the sources of heterogeneity. For the study of TNF-α-308G/A rs1800629 polymorphism and RA susceptibility, subgroup analysis by geographical region showed no significant statistical significance in the overall and subgroup results of the five gene models. For the study of TNF-α-308G/A rs1800629 polymorphisms and RA severity, the overall results of the five gene models were not statistically significant, but TNF-α-308G/A rs1800629 polymorphisms were observed to be significantly associated with the severity of RA in the European population after subgroup analysis; therefore, geographical regions may be the source of heterogeneity in TNF-α-308G/A rs1800629 polymorphisms and RA severity studies. In both studies, sensitivity analyses were performed using the two methods. First, a sensitivity analysis was conducted by eliminating them individually. The results showed no significant change in the OR or 95% CI values for the overall outcome after the sequential removal of each study. Second, Stata 17.0 software performed a sensitivity analysis of the results of the meta-analysis. The results revealed that none of the 34 studies on RA susceptibility affected the stability of the results (Fig. 4). Similarly, none of the six studies on the severity of RA affected the stability of the results (Fig. 5). The results of sensitivity analysis indicated that the present meta-analysis was reliable.
Analysis of publication bias. In the study of TNF-α-308G/A rs1800629 polymorphisms and susceptibility to RA, the funnel plot method was used to test for publication bias. A publication bias funnel plot, which is visually asymmetric, is illustrated in Fig. 6, and there may be bias. After the Egger method test, P>0.05 in all genetic models indicated that there was no publication bias in the present study, and the detailed data are presented in Table IV. For the study of TNF-α-308G/A rs1800629 polymorphisms and RA severity, no publication bias funnel was used for publication bias because the number of studies was <10. Publication bias was assessed using Egger's test. According to the results of the Egger test, P>0.05 in all genetic models indicated that there was no publication bias in the present study. Detailed data is listed in Table V.
Positive result confidence test. Based on the OR value and 95% CI of the aforementioned results, the false-positive report probability (FPRP) values of the dominant and super-dominant models were calculated under a series of prior probability conditions, and the results are shown in Table VI. An FPRP value of <0.2 was used as the standard to judge the reliability of the correlation (42). Confidence assessment determined that the statistically significant association in this meta-analysis was reliable for TNF-α-308G/A rs1800629.
Discussion
RA is a typical chronic inflammatory disease, and genetic factors are extremely important in the pathogenesis of RA. Individuals with predisposing genes are exposed to specific environments that cause immune regulation in the body, thereby triggering the entire inflammatory process. During this process, the oxidative stress that occurs in the body accelerates the inflammatory process, aggravates immune system disorders and promotes the occurrence of diseases (43). In addition, RA is a heterogeneous disease, and genetic and environmental factors influence its incidence in different ethnic groups. According to the current results, genetic heterogeneity is manifested by different susceptibility gene loci in different races, and even if individual sites are the same, allele frequency and genetic contribution are different (44).
The TNF-α gene, located in a highly polymorphic region, human chromosome 6 short arm 6p21.3, is a pro-inflammatory cytokine produced primarily by macrophages and monocytes and is involved in normal inflammatory and immune responses (45). TNF-α has two different receptors (TNFR1 and TNFR2). TNF-α binds to cell surface TNFR1 and TNFR2, respectively, to regulate apoptosis, proliferation and differentiation. Most cell surfaces express TNFR1; however, TNFR2 expression is limited to immune cells (46). TNF-α has numerous biological effects, such as activation, proliferative and differentiation of immune cells; inducing apoptosis in certain non-tumor cells and most tumor cells; playing an important role in antitumor, immune defense and inflammatory response; and is an important biological mediator for maintaining the immune balance of the body (47). TNF can be detected in the synovial fluid of patients with RA; therefore, it is important to investigate whether there is an association between TNF-α-308G/A rs1800629 gene polymorphisms and RA susceptibility and severity. The results of Jahid et al (4) demonstrated that TNF-α-308G/A rs1800629 was strongly associated with the onset of RA in the Indian population. Li et al (26) showed that TNF-α-308G/A rs1800629 gene polymorphisms were significantly associated with the occurrence of RA in the Han Chinese population. By contrast, the results of Sun et al (6) demonstrated that TNF-α-308G/A rs1800629 gene polymorphisms are not associated with the pathogenesis of RA. In addition, Boechat et al (5) reported through a controlled study of 131 patients with RA and 192 healthy volunteers that TNF-α-308G/A rs1800629 gene polymorphisms in the Brazilian population were not associated with the occurrence of RA but were related to the severity of the disease. Nemec et al (30) reported that patients with RA and the GG genotype of the promoter polymorphism of the TNF-α-308G/A rs1800629 had a more severe disease course. In addition, they observed that the G allele of the TNF-α-308G/A rs1800629 promoter polymorphism in this cohort was associated with decreased functional ability in patients with RA. In a previous meta-analysis, Song et al (48) included 19 studies suggesting that TNF-α-308G/A rs1800629 gene polymorphisms are associated with susceptibility to RA. This meta-analysis excluded the literature that the genotype frequency of the control group did not conform to HWE, included a total of 34 relevant literature, analyzed by five gene models, and finally reported that TNF-α-308G/A rs1800629 gene polymorphisms were associated with the severity of RA in the European population in the dominant model and the super-dominant model, and the results were reliable after FPRP testing.
The present meta-analysis had certain limitations. First, the current study included 34 articles, but the sample size of certain single nucleotide polymorphism analyses was small, and most of them were single-center studies. More high-quality, multicenter and large-sample studies are required for further analysis and verification. Second, a few studies did not provide long-term follow-up data, making it difficult to assess the durability and stability of the results. Thirdly, in the subgroup analyses, the sample sizes were insufficient for a few ethnic groups, resulting in a slight lack of diversity in the results. Fourth, only the relationship between TNF-α-308G/A rs1800629 gene polymorphisms and the susceptibility and severity of RA was studied, and further research on other related genes is necessary to fully elucidate the pathogenesis of RA. Fifth, meta-analysis is a descriptive secondary analysis that builds on existing research; therefore, the heterogeneity of the selected literature, study design of variables, different judgment criteria and statistical methods may affect the results of the meta-analysis.
In summary, it was observed that TNF-α-308G/A rs1800629 gene polymorphisms were not associated with susceptibility to RA. However, TNF-α-308G/A rs1800629 gene polymorphisms were significantly associated with the severity of RA in the European population, and FPRP testing suggested reliable results.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study are included in the figures and/or tables of this article.
Authors' contributions
YLW and XYL participated in the design of the present study, and both performed statistical analyses. LL and SFL conducted the study and collected important background information. PFH and XDL drafted the manuscript. All authors read and approved the final manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
All procedures involving human participants performed in the present study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, formal consent was not required.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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