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The association between TNF-α promoter polymorphisms and ankylosing spondylitis: a meta-analysis

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Abstract

The relationship of TNF-α promoter polymorphisms and ankylosing spondylitis (AS) has been reported with conflicting results. We perform this meta-analysis to collect all the relevant studies up to date to further clarify the association of TNF-α promoter polymorphisms with AS. A review was conducted of studies reporting on the association between TNF-α promoter polymorphisms and AS susceptibility in Medline, Pubmed, Embase, and Web of Science. The numbers of individuals with various genotypes and alleles in both the case and control groups were extracted from relevant studies. Odds ratios (ORs) with 95% confidence interval (CI) were used to estimate the association. Fourteen eligible studies, contributing data on 3,880 subjects (1,766 patients; 2,114 controls), were included in this meta-analysis. The ORs of various comparisons indicated that there was no association between TNF-α 238, 308 polymorphisms, and AS susceptibility in the overall population. For HLA-B27+ population, although the frequency of 308 A allele decreased in AS patients (OR = 0.721; 95%CI = 0.522–0.995), the result was no longer statistically significant after excluding the Hardy–Weinberg equilibrium violation studies (OR = 1.150; 95%CI = 0.568–2.310). No relationship was found between TNF-α promoter 238 polymorphisms and AS in HLA-b27+ population. No association was found between TNF-α promoter 238/308 polymorphisms and ankylosing spondylitis susceptibility in both the overall and HLA-B27+ population.

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References

  1. Brewerton DA, Hart FD, Nicholls A, Caffrey M, James DC, Sturrock RD (1973) Ankylosing spondylitis and HL-A 27. Lancet 1:904–907

    Article  CAS  PubMed  Google Scholar 

  2. Khan MA, Ball EJ (2002) Genetic aspects of ankylosing spondylitis. Best Pract Res Clin Rheumatol 16:675–690

    CAS  PubMed  Google Scholar 

  3. Rubin LA, Amos CI, Wade JA et al (1994) Investigating the genetic basis for ankylosing spondylitis. Linkage studies with the major histocompatibility complex region. Arthritis Rheum 37:1212–1220

    Article  CAS  PubMed  Google Scholar 

  4. van der Linden SM, Valkenburg HA, de Jongh BM, Cats A (1984) The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum 27:241–249

    Article  PubMed  Google Scholar 

  5. Benjamin R, Parham P (1990) Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol Today 11:137–142

    Article  CAS  PubMed  Google Scholar 

  6. Tracey KJ, Cerami A (1993) Tumor necrosis factor: an updated review of its biology. Crit Care Med 21:S415–S422

    Article  CAS  PubMed  Google Scholar 

  7. Glossop JR, Nixon NB, Dawes PT, Hassell AB, Mattey DL (2003) No association of polymorphisms in the tumor necrosis factor receptor I and receptor II genes with disease severity in rheumatoid arthritis. J Rheumatol 30:1406–1409

    CAS  PubMed  Google Scholar 

  8. Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Putte LB, Duff GW (1993) An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA a1, B8, and DR3 alleles. J Exp Med 177:557–560

    Article  CAS  PubMed  Google Scholar 

  9. D'Alfonso S, Richiardi PM (1994) A polymorphic variation in a putative regulation box of the TNFa promoter region. Immunogenetics 39:150–154

    PubMed  Google Scholar 

  10. Lee YH, Song GG (2009) Lack of association of TNF-alpha promoter polymorphisms with ankylosing spondylitis: a meta-analysis. Rheumatology (Oxford) 48:1359–1362

    Article  CAS  Google Scholar 

  11. Chatzikyriakidou A, Georgiou I, Voulgari PV, Drosos AA (2009) The role of tumor necrosis factor (TNF)-alpha and TNF receptor polymorphisms in susceptibility to ankylosing spondylitis. Clin Exp Rheumatol 27:645–648

    CAS  PubMed  Google Scholar 

  12. Lu MC, Yang KL, Tung CH et al (2008) Higher LPS-stimulated TNF-alpha mRNA levels in peripheral blood mononuclear cells from Chinese ankylosing spondylitis patients with −308G/A polymorphism in promoter region of tumor necrosis factor: association with distinct A33/B58/Cw10 haplotypes. Rheumatol Int 29:189–195

    Article  CAS  PubMed  Google Scholar 

  13. Nicknam MH, Mahmoudi M, Amirzargar AA, Jamshidi AR, Rezaei N, Nikbin B (2009) HLA-B27 subtypes and tumor necrosis factor alpha promoter region polymorphism in Iranian patients with ankylosing spondylitis. Eur Cytokine Netw 20:17–20

    CAS  PubMed  Google Scholar 

  14. Shiau MY, Lo MK, Chang CP, Yang TP, Ho KT, Chang YH (2007) Association of tumour necrosis factor alpha promoter polymorphisms with ankylosing spondylitis in Taiwan. Ann Rheum Dis 66:562–563

    Article  CAS  PubMed  Google Scholar 

  15. Sousa E, Caetano-Lopes J, Pinto P et al (2009) Ankylosing spondylitis susceptibility and severity—contribution of TNF gene promoter polymorphisms at positions −238 and −308. Ann N Y Acad Sci 1173:581–588

    Article  CAS  PubMed  Google Scholar 

  16. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748

    CAS  PubMed  Google Scholar 

  17. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  CAS  PubMed  Google Scholar 

  18. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

  19. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  PubMed  Google Scholar 

  20. Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    CAS  PubMed  Google Scholar 

  21. Aguillon JC, Cruzat A, Aravena O, Salazar L, Llanos C, Cuchacovich M (2006) Could single-nucleotide polymorphisms (SNPs) affecting the tumour necrosis factor promoter be considered as part of rheumatoid arthritis evolution? Immunobiology 211:75–84

    Article  CAS  PubMed  Google Scholar 

  22. De Vos M (2004) Review article: joint involvement in inflammatory bowel disease. Aliment Pharmacol Ther 20(Suppl 4):36–42

    Article  PubMed  Google Scholar 

  23. Rudwaleit M, Hohler T (2001) Cytokine gene polymorphisms relevant for the spondyloarthropathies. Curr Opin Rheumatol 13:250–254

    Article  CAS  PubMed  Google Scholar 

  24. Field M (2001) Tumour necrosis factor polymorphisms in rheumatic diseases. QJM 94:237–246

    Article  CAS  PubMed  Google Scholar 

  25. Seitz M, Wirthmuller U, Moller B, Villiger PM (2007) The −308 tumour necrosis factor-alpha gene polymorphism predicts therapeutic response to TNFalpha-blockers in rheumatoid arthritis and spondyloarthritis patients. Rheumatology (Oxford) 46:93–96

    Article  CAS  Google Scholar 

  26. Fraile A, Nieto A, Beraun Y, Vinasco J, Mataran L, Martin J (1998) Tumor necrosis factor gene polymorphisms in ankylosing spondylitis. Tissue Antigens 51:386–390

    CAS  PubMed  Google Scholar 

  27. Gonzalez S, Torre-Alonso JC, Martinez-Borra J et al (2001) TNF-238a promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients. J Rheumatol 28:1288–1293

    CAS  PubMed  Google Scholar 

  28. Hohler T, Schaper T, Schneider PM, Meyer ZBK, Marker-Hermann E (1998) Association of different tumor necrosis factor alpha promoter allele frequencies with ankylosing spondylitis in HLA-B27 positive individuals. Arthritis Rheum 41:1489–1492

    Article  CAS  PubMed  Google Scholar 

  29. Kaijzel EL, Brinkman BM, van Krugten MV et al (1999) Polymorphism within the tumor necrosis factor alpha (TNF) promoter region in patients with ankylosing spondylitis. Hum Immunol 60:140–144

    Article  CAS  PubMed  Google Scholar 

  30. Martinez-Borra J, Gonzalez S, Lopez-Vazquez A et al (2000) HLA-B27 alone rather than B27-related class I haplotypes contributes to ankylosing spondylitis susceptibility. Hum Immunol 61:131–139

    Article  CAS  PubMed  Google Scholar 

  31. McGarry F, Walker R, Sturrock R, Field M (1999) The −308.1 polymorphism in the promoter region of the tumor necrosis factor gene is associated with ankylosing spondylitis independent of HLA-B27. J Rheumatol 26:1110–1116

    CAS  PubMed  Google Scholar 

  32. Milicic A, Lindheimer F, Laval S et al (2000) Interethnic studies of tnf polymorphisms confirm the likely presence of a second mhc susceptibility locus in ankylosing spondylitis. Genes Immun 1:418–422

    Article  CAS  PubMed  Google Scholar 

  33. Vargas-Alarcon G, Casasola-Vargas J, Rodriguez-Perez JM et al (2006) Tumor necrosis factor-alpha promoter polymorphisms in Mexican patients with spondyloarthritis. Hum Immunol 67:826–832

    Article  CAS  PubMed  Google Scholar 

  34. Verjans GM, Brinkman BM, Van Doornik CE, Kijlstra A, Verweij CL (1994) Polymorphism of tumour necrosis factor-alpha (TNF-alpha) at position −308 in relation to ankylosing spondylitis. Clin Exp Immunol 97:45–47

    CAS  PubMed  Google Scholar 

  35. van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis, A proposal for modification of the New York criteria. Arthritis Rheum 27:361–368

    Article  PubMed  Google Scholar 

  36. Moll JM, Wright V (1973) New York clinical criteria for ankylosing spondylitis. A statistical evaluation. Ann Rheum Dis 32:354–363

    Article  CAS  PubMed  Google Scholar 

  37. Reveille JD (1993) The interplay of nature versus nurture in predisposition to the rheumatic diseases. Rheum Dis Clin North Am 19:15–27

    CAS  PubMed  Google Scholar 

  38. Pei J, Choo SY, Spies T, Strominger JL, Hansen JA (1991) Association of four HLA class III region genomic markers with HLA haplotypes. Tissue Antigens 37:191–196

    Article  CAS  PubMed  Google Scholar 

  39. Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP (2006) Impact of violations and deviations in Hardy–Weinberg equilibrium on postulated gene–disease associations. Am J Epidemiol 163:300–309

    Article  PubMed  Google Scholar 

  40. Goie TH, Steven MM, van der Linden SM, Cats A (1985) Evaluation of diagnostic criteria for ankylosing spondylitis: a comparison of the Rome, New York and modified New York criteria in patients with a positive clinical history screening test for ankylosing spondylitis. Br J Rheumatol 24:242–249

    Article  Google Scholar 

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Li, B., Wang, P. & Li, H. The association between TNF-α promoter polymorphisms and ankylosing spondylitis: a meta-analysis. Clin Rheumatol 29, 983–990 (2010). https://doi.org/10.1007/s10067-010-1499-y

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