Meta-analysis of TNF-alpha promoter −308 A/G polymorphism and SLE susceptibility. Eur J Hum Genet

Division of Rheumatology, Korea University, Seoul, Korea.
European Journal of HumanGenetics (Impact Factor: 4.35). 04/2006; 14(3):364-71. DOI: 10.1038/sj.ejhg.5201566
Source: PubMed


Alleles of tumor necrosis factor-alpha (TNF-alpha) gene have been inconsistently associated with systemic lupus erythematosus (SLE), particularly the 308-A/G functional promoter polymorphism. To generate large-scale evidence on whether 308-A/G promoter polymorphism is associated with SLE susceptibility we have conducted a meta-analysis. We have identified 21 studies of this polymorphism and SLE using MEDLINE search. Meta-analysis was performed for genotypes A/A (recessive effect), A/A+A/G (dominant effect), and A allele in fixed or random effects models. All control samples were in Hardy-Weinberg proportion. The overall odds ratio (OR) of the A/A genotype was 3.2 (95% CI=2.0-5.3, P<0.001). Stratification by ethnicity indicated that the A/A genotype was associated with SLE in European-derived population (OR=4.0, CI=2.5-6.4, P<0.001). No association was detected in Asian-derived population (OR, 1.3, CI=0.3-6.3, P=0.76). The overall OR for the risk genotypes (A/A and A/G) was 2.0 (CI=1.3-3.1, P<0.001). Similar results were found between the risk allele A and SLE where a significant association was found in European population (OR=2.1, CI=1.6-2.7, P<0.001), but not in Asian (OR=1.4, CI=0.8-2.3, P=0.2) or African (OR=1.2, CI=0.6-2.5, P=0.59) populations. In summary, this meta-analysis demonstrates that the TNF-alpha promoter -308 A/G polymorphism may confer susceptibility to SLE, especially in European-derived population.

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    • "TNF-α-308A/G polymorphism is the most common polymorphism in the promoter. This polymorphism could influence cytokine production [44]–[46], and the TNF-α promoter-308A/G polymorphism had been reported to be associated with several autoimmune disorders [47]–[48]. TNF-α-308A allele had shown to be a stronger transcriptional activator than the common TNF-α-308G allele in vitro, and patients with TNF-α-308GA heterozygosity had increased TNF production [44], [49]. Although a possible association of the TNF-α-308A/G polymorphism with risk of DM was reported, and it was still unknown whether there was a significant association between TNF-α-308A/G polymorphism and the susceptibility to DM [10]–[17]. "
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    ABSTRACT: Background Some surveys had inspected the effects of the tumor necrosis factor-α (TNF-α)-308A/G polymorphism on susceptibility to dermatomyositis (DM), and showed mixed results. To briefly review these consequences, a comprehensive meta-analysis was carried out to estimate the relationship between them much more accurately. Methods Relevant documents dated to February 2014 were acquired from the PUBMED, MEDLINE, and EMBASE databases. The number of the genotypes and/or alleles for the TNF-α-308A/G in the DM and control subjects was extracted and statistical analysis was conducted using STATA 11.2 software. Summary odds ratios (ORs) with their 95% confidence intervals (95% CIs) were used to calculate the risk of DM with TNF-α-308A/G. Stratified analysis based on ethnicity and control population source was also performed. Results 555 patients with DM and 1005 controls from eight published investigations were finally involved in this meta-analysis. Combined analysis revealed that the overall ORs for the TNF-α-308A allele were 2.041 (95% CIs 1.528–2.725, P<0.0001) in DM. Stratification by ethnicity indicated the TNF-α-308A allele polymorphism was found to be significantly associated with DM in Europeans (OR = 1.977, 95% CI 1.413–2.765, P<0.0001). The only study conducted on TNF-α-308A/G polymorphism in Asians could not be used in ethnicity-stratified meta-analysis. Meta-analysis of the AA+AG vs. GG (dominant model) and AA vs. GG (additive model) of this polymorphism revealed a significant association with DM in overall populations and Europeans. Conclusions Our meta-analysis demonstrated that the TNF-α-308A/G polymorphism in the TNF gene might contribute to DM susceptibility, especially in European population. However, further studies with large sample sizes and among different ethnicity populations should be required to verify the association.
    PLoS ONE 08/2014; 9(8):e102841. DOI:10.1371/journal.pone.0102841 · 3.23 Impact Factor
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    • "A meta-analysis showed significant susceptibility from TNF-a -308 promoter G/A polymorphism in the European SLE patients but not in Asian or African. The finding of the different association according to ethnicity is somewhat surprising and needs the explanation of why it is not associated in non-Europeans [2]. There were no other significant differences in the characteristic features of the patients according to the promoter genes. "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a disorder of immune regulation where cytokine imbalance and genetic factors are implicated in its pathogenesis.Aim of the workTo evaluate the clinical significance of serum levels of tumor necrosis factor alpha (TNFα) and its -308 G/A promoter polymorphism as well as the IL-6 and -174 promoter polymorphism in SLE patients and find any association to the clinical and laboratory features as well as to the disease activity and severity.Patients and methodsWe studied 37 female SLE patients and age and gender matched healthy control. Demographic, clinical and serological data were evaluated and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaboration Clinics/ACR Damage Index (SLICC) were assessed. Serum TNF-α and IL-6 levels were measured using enzyme-linked immunosorbent assay (ELISA) and DNA genotyped for TNF-α promoter (-308 G/A) and IL-6 promoter (-174 G/C) by polymerase-chain reaction-restriction fragment-length polymorphism (PCR-RFLP) analysis.ResultsSerum TNF-α and IL-6 levels were significantly higher in the SLE patients compared to control. Regarding IL-6, there was a statistically significant difference between the levels in the three groups according to the promoter polymorphisms. Patients with constitutional symptoms showed higher level of IL-6 while the TNF-α level was significantly lower in those with pulmonary manifestations. There was a tendency to a higher TNF-α and IL-6 level in those with neuropsychiatric manifestations.Conclusion Serum TNF-α, -308 G/A promoter polymorphism, IL-6 and -174 G/C were higher in SLE patients than in healthy controls. To confirm our results we propose that larger scale, multicenter studies with longer evaluation periods are needed.
    Egyptian Rheumatologist 07/2012; 34(3):119-125. DOI:10.1016/j.ejr.2012.05.003
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    • "Analyses of other polymorphic genes related to autoimmune response and inflammation have been carried out. Results indicated that PTPN22 1858T/C [25] and TNF-α-308G/A [31, 58, 59] alleles are associated with SLE, SS, and T1D. Likewise, the CTLA4 gene has been reported as a risk factor for AIH, T1D, and RA [37, 60, 61]. "
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    ABSTRACT: The prevalence and genetic susceptibility of autoimmune diseases (ADs) may vary depending on latitudinal gradient and ethnicity. The aims of this study were to identify common human leukocyte antigen (HLA) class II alleles that contribute to susceptibility to six ADs in Latin Americans through a meta-analysis and to review additional clinical, immunological, and genetic characteristics of those ADs sharing HLA alleles. DRB1(∗)03:01 (OR: 4.04; 95%CI: 1.41-11.53) was found to be a risk factor for systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and type 1 diabetes mellitus (T1D). DRB1(∗)04:05 (OR: 4.64; 95%CI: 2.14-10.05) influences autoimmune hepatitis (AIH), rheumatoid arthritis (RA), and T1D; DRB1(∗)04:01 (OR: 3.86; 95%CI: 2.32-6.42) is a susceptibility factor for RA and T1D. Opposite associations were found between multiple sclerosis (MS) and T1D. DQB1(∗)06:02 and DRB1(∗)15 alleles were risk factors for MS but protective factors for T1D. Likewise, DQB1(∗)06:03 allele was a risk factor for AIH but a protective one for T1D. Several common autoantibodies and clinical associations as well as additional shared genes have been reported in these ADs, which are reviewed herein. These results indicate that in Latin Americans ADs share major loci and immune characteristics.
    04/2012; 2012(2):569728. DOI:10.1155/2012/569728
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