Gastric cancer (GC) is commonly diagnosed with malignancies and remained a considerable health problem [1]. Tumor necrosis factor-alpha (TNF-α) produced by macrophages is a cytokine playing a pivotal role in the pathogenesis of malignant diseases [2]. TNF-α is a pro-inflammatory cytokine involved in the growth, differentiation, and survival of many cells. TNF-α is also playing an important role in the pathogenesis of cancer [3]. Studies have shown that TNF-α promoter polymorphism-308 (rs1800629) may regulate TNF-α production [4]. TNF-α-308 has been confirmed as a risk factor for a range of cancers such as breast, gastric, and hepatocellular cancers [5, 6]. Several single-nucleotide polymorphisms have been identified in the promoter region of TNF-α. TNF-α-308 G>A is a mediator of immune response and it shares many biological properties with interleukin 1 (IL-1). TNF-α-308 A allele is an important candidate accounting for the increased risk of gastric carcinoma [7, 8]. TNF-α-857 C>T is associated with higher transcriptional activity [9].
The number of TNF-α single nucleotide polymorphisms in promoter has been indicated to regulate TNF-α transcription [10, 11]. TNF-α-308 is an extensively studied single-nucleotide polymorphism in GCs [12,13,14]. The results on TNF-α-308 G>A have been inconsistent. Therefore, a meta-analysis was conducted to find out the association of TNF-α-308 G>A and GC.
Pubmed and Google databases were used to extract all relevant literature on human studies, TNF-α polymorphism. Data from eligible studies were identified with respect to year of publication, first author name, country, source of sample, cases and controls, genotype frequencies, and reported associations. This study has a total of 12 articles on TNF-α-308 G>A and GC. Data on the author's last name, publication year, country of origin, study population source, genotypes, number of cases and controls, and TNF-α-308 genotyping method were extracted. Data were procured independently from each study using a predefined form and conflicts were resolved by discussion as shown in
Flow chart of studies identification and inclusion.
The genotype frequency and distribution among controls and cases were analyzed by Fisher's test.
Twelve studies were analyzed in which 12 sets of data were compared with distributions of TNF-α-308 genotypes in patients and healthy controls.
Analysis using Fischer's exact test revealed that TNF-α-308 GA genotype was significantly prevalent in GC cases compared with healthy controls [
Distribution of TNF-α-308 G>A (rs1800629) genotypes in GC patients and healthy controls
GG | 3,200 | 4,300 | Reference | – |
GA | 891 | 806 | 0.82 (0.74–0.91) | <0.0001 |
AA | 66 | 79 | 0.62 (0.44–0.86) | 0.49 |
GG, homozygous wild; GA, heterozygous; AA, homozygous variant; TNF-α, tumor necrosis factor-alpha; GC, gastric cancer; OR, odds ratio; CI, confidence interval.
Main characteristics of studies selected for meta-analysis and distribution of TNF-α-308 G>A (rs1800629) polymorphism in cases and healthy controls
Li-Chuan Du et al. (2017) | China | 204 | 184 | 12 | 326 | 60 | 14 |
Paulo Canedo et al. (2008) | Portugal | 330 | 178* | 544 | 169* | ||
Wu et al. (2002) | USA | 144 | 4 | 2 | 214 | 4 | 2 |
Liping Jiang et al. (2017) | China | 207 | 30 | 3 | 411 | 95 | 4 |
Yan Hong et al. (2013) | China | 1335 | 333 | 18 | 1585 | 295 | 14 |
David Stubljar et al. (2014) | Slovenia | 63 | 20 | 0 | 83 | 22 | 3 |
Amar C Bhayal et al. (2013) | India | 32 | 76 | 6 | 76 | 128 | 25 |
Garcia-Gonzalez et al. (2007) | Spain | 309 | 84 | 11 | 320 | 77 | 7 |
Sugimoto et al. (2007) | Japan | 101 | 4 | 0 | 169 | 3 | 0 |
Wanli Lu et al. (2005) | China | 214 | 36 | 0 | 274 | 24 | 2 |
Carlos Machado et al. (2003) | Portugal | 179 | 105 | 3 | 231 | 69 | 4 |
Seilanian Toosi M et al. (2007) | Iran | 82 | 15 | 11 | 67 | 29 | 4 |
(GA + AA).
Statistics to test publication bias and heterogeneity in the meta-analysis
12 | GG (3,200/4,300) | 0.508 | 0.39 | 1.65 | (0.98–2.76) | 1.90 | 0.056 | 222.03 | 0.00 | 95.04 |
11 | GA (891/806) | –0.291 | 0.95 | 0.74 | (0.48–1.15) | –1.30 | 0.19 | 109.14 | 0.00 | 90.83 |
10 | AA* (66/79) | 0.009 | 0.56 | 1.01 | (0.71–1.43) | 0.57 | 0.95 | 9.39 | 0.40 | 4.23 |
12 | GG + GA (1,135/1,054) | –0.308 | 0.95 | 0.73 | (0.51–1.04) | –1.73 | 0.082 | 100.59 | 0.00 | 89.06 |
Chi-square
Fixed-effects model.
P for the
Higgins
CI, confidence interval; RE, random effect; OR, odds ratio.
The TNF-α-308 GG genotype distribution in patients and controls was 3,200/4,300. Significant heterogeneity among studies with
TNF-α-308 GA genotype distribution in patients and controls was 891/806 and significant heterogeneity with
TNF-α-308 AA genotype distribution in patients and controls was 66/79. Nonsignificant heterogeneity with
TNF-α-308 GA + AA genotype distribution in patients and controls was 1,135/1,054. Significant heterogeneity with
Begg's funnel plot and Egger's test were used to assess publication bias and results did not indicate evidence of publication bias for TNF-α-308 polymorphisms in cases and controls [(TNF-α-308 GG Begg's test,
Inflammation is considered as one of the key factors involving in the pathogenesis of cancer, and TNF-α is believed to be one of the most crucial inflammatory cytokines. TNF-α G>A is produced by macrophages, neutrophils, fibroblasts, T-cells, B-cells, and tumor cells, and it has been reported to play an important role in the pathogenesis of cancer [3, 15]. The transcription of TNF-α is regulated under genetic control. Studies have indicated that promoter polymorphisms at rs361525, rs1800629, rs1799724, and rs1799964 may regulate TNF-α production and it was reported that expression level of TNF-α was proved to be affected by polymorphisms in the promoter region of TNF [4, 16, 17]. Results of meta-analysis showed an overall nonsignificant association of TNF-α-308 GG, GA, AA, and GA + AA genotypes with GC. The discrepancy in results could be identified in sample size, ethnicity, or etiological factors that contribute to the heterogeneity.
Several meta-analyses on TNF-α-308 G>A polymorphism showed an association of TNF-α-308 G>A genotypes with GC risk [18, 19]. Overall results on TNF-α-308 G>A genotypes did not show the association between AA genotype and GC risk using GG as the reference genotype yielded statistically significant risk of GC with TNF-α-308 GA genotype. However, the meta-analysis was conducted using fixed-and random-effects models; none of the TNF-α-308 G>A genotypes showed significant association with GC. Earlier studies suggested that frequencies of genetic markers often show high variations among various ethnic and racial groups whereas differences in genetic effects in terms of ORs are much less common [20]. Heterogeneity between studies was high for TNF-α-308 genotypes and low for TNF-α-308 AA genotype, as indicated by the
To understand the carcinogenesis of GC, prospective studies in combination with the analysis of other cytokines are required. Earlier identification of TNF-α polymorphisms yielded some suggestions on understanding the genetic predisposition of gastric and colorectal cancers [22].
Taken together, meta-analysis data do not support the association between TNF-α-308 genotypes (GG, GA, AA, and GA + AA) and GC predisposition. However, additional case–control studies in different populations are still needed.