Molecular Biology Reports

, Volume 40, Issue 11, pp 6303–6308 | Cite as

MMP-2, TNF-α and NLRP1 polymorphisms in Chinese patients with ankylosing spondylitis and rheumatoid arthritis



Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are autoimmune, inflammatory diseases with substantial genetic contributions. Matrix metalloproteinase (MMP)-2, tumor necrosis factor (TNF)-α and NLR family pyrin domain-containing 1 (NLRP1) play important roles in the immune response. We studied the MMP-2 rs243865 C/T, TNF-α rs1800629 A/G, NLRP1 rs878329 C/G and NLRP1 rs6502867 C/T polymorphisms in a Chinese cohort of 520 patients with RA, 100 with AS and 520 controls. Genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Using the MMP-2 rs243865 CC homozygote genotype as the reference group, the CT and TT/CT genotypes were associated with significantly reduced risks of AS. However, logistic regression analyses revealed that the MMP-2 rs243865 C/T polymorphism was not associated with risk of RA. TNF-α rs1800629 A/G, NLRP1 rs878329 C/G and NLRP1 rs6502867 C/T polymorphisms were not associated with risk of RA or AS. These findings suggest that the MMP-2 rs243865 C/T polymorphism is associated with AS development.


MMP-2 Polymorphism Ankylosing spondylitis Rheumatoid arthritis Molecular epidemiology 



Confidence interval


Linkage disequilibrium


Matrix metalloproteinase-2


NLR family pyrin domain-containing 1


Odds ratio


Single nucleotide polymorphism


Tumor necrosis factor-α



This study was supported in part by National Natural Science Foundation of China (81371927) and Nanjing Medical University Foundation for Development of Science and Technology (06NMUZ045, 2012NJMU128).

Conflict of interest

None of the authors has any potential financial conflict of interest related to this manuscript.


  1. 1.
    Braun J, Sieper J (2007) Ankylosing spondylitis. Lancet 369:1379–1390PubMedCrossRefGoogle Scholar
  2. 2.
    Plenge RM, Seielstad M, Padyukov L et al (2007) TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study. N Engl J Med 357:1199–1209PubMedCrossRefGoogle Scholar
  3. 3.
    Giannelli G, Erriquez R, Iannone F et al (2004) MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in patients with rheumatoid arthritis and psoriatic arthritis. Clin Exp Rheumatol 22:335–338PubMedGoogle Scholar
  4. 4.
    Parks WC, Wilson CL, Lopez-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4:617–629PubMedCrossRefGoogle Scholar
  5. 5.
    Huang H, Zhao W, Tang Z et al (2009) Characterization of porcine MMP-2 and its association with immune traits. Gene 435:63–71PubMedCrossRefGoogle Scholar
  6. 6.
    Yoshihara Y, Nakamura H, Obata K et al (2000) Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis. Ann Rheum Dis 59:455–461PubMedCrossRefGoogle Scholar
  7. 7.
    Konttinen YT, Ainola M, Valleala H et al (1999) Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis. Ann Rheum Dis 58:691–697PubMedCrossRefGoogle Scholar
  8. 8.
    Hot A, Zrioual S, Lenief V, Miossec P (2012) IL-17 and tumour necrosis factor alpha combination induces a HIF-1alpha-dependent invasive phenotype in synoviocytes. Ann Rheum Dis 71:1393–1401PubMedCrossRefGoogle Scholar
  9. 9.
    Itoh T, Matsuda H, Tanioka M et al (2002) The role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis. J Immunol 169:2643–2647PubMedGoogle Scholar
  10. 10.
    Corry DB, Rishi K, Kanellis J et al (2002) Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2-deficiency. Nat Immunol 3:347–353PubMedCrossRefGoogle Scholar
  11. 11.
    Li G, Zhang Y, Qian Y et al (2013) Interleukin-17A promotes rheumatoid arthritis synoviocytes migration and invasion under hypoxia by increasing MMP2 and MMP9 expression through NF-kappaB/HIF-1alpha pathway. Mol Immunol 53:227–236PubMedCrossRefGoogle Scholar
  12. 12.
    Price SJ, Greaves DR, Watkins H (2001) Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: role of Sp1 in allele-specific transcriptional regulation. J Biol Chem 276:7549–7558PubMedCrossRefGoogle Scholar
  13. 13.
    Chang YH, Lin IL, Tsay GJ et al (2008) Elevated circulatory MMP-2 and MMP-9 levels and activities in patients with rheumatoid arthritis and systemic lupus erythematosus. Clin Biochem 41:955–959PubMedCrossRefGoogle Scholar
  14. 14.
    Hitchon CA, Danning CL, Illei GG, El-Gabalawy HS, Boumpas DT (2002) Gelatinase expression and activity in the synovium and skin of patients with erosive psoriatic arthritis. J Rheumatol 29:107–117PubMedGoogle Scholar
  15. 15.
    Nell VP, Machold KP, Eberl G et al (2004) Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford) 43:906–914CrossRefGoogle Scholar
  16. 16.
    Lee YH, Bae SC, Choi SJ, Ji JD, Song GG (2012) Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis. Mol Biol Rep 39(12):10627–10635PubMedCrossRefGoogle Scholar
  17. 17.
    Bouma G, Crusius JB, Oudkerk Pool M et al (1996) Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease. Scand J Immunol 43:456–463PubMedCrossRefGoogle Scholar
  18. 18.
    Louis E, Franchimont D, Piron A et al (1998) Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 113:401–406PubMedCrossRefGoogle Scholar
  19. 19.
    Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417–426PubMedCrossRefGoogle Scholar
  20. 20.
    Jin Y, Mailloux CM, Gowan K et al (2007) NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 356:1216–1225PubMedCrossRefGoogle Scholar
  21. 21.
    Jin Y, Birlea SA, Fain PR, Spritz RA (2007) Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population. J Invest Dermatol 127:2558–2562PubMedCrossRefGoogle Scholar
  22. 22.
    Jin Y, Riccardi SL, Gowan K, Fain PR, Spritz RA (2010) Fine-mapping of vitiligo susceptibility loci on chromosomes 7 and 9 and interactions with NLRP1 (NALP1). J Invest Dermatol 130:774–783PubMedCrossRefGoogle Scholar
  23. 23.
    Magitta NF, Boe Wolff AS, Johansson S et al (2009) A coding polymorphism in NALP1 confers risk for autoimmune Addison’s disease and type 1 diabetes. Genes Immun 10:120–124PubMedCrossRefGoogle Scholar
  24. 24.
    Sui J, Li H, Fang Y et al (2012) NLRP1 gene polymorphism influences gene transcription and is a risk factor for rheumatoid arthritis in han chinese. Arthritis Rheum 64:647–654PubMedCrossRefGoogle Scholar
  25. 25.
    Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324PubMedCrossRefGoogle Scholar
  26. 26.
    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 27:361–368PubMedCrossRefGoogle Scholar
  27. 27.
    Cheng J, Zhang H, Zhuang C, Liu R (2012) Peptidylarginine deiminase type 4 and methyl-CpG binding domain 4 polymorphisms in Chinese patients with rheumatoid arthritis. J Rheumatol 39:1159–1165PubMedCrossRefGoogle Scholar
  28. 28.
    Veidal SS, Larsen DV, Chen X et al (2012) MMP mediated type V collagen degradation (C5 M) is elevated in ankylosing spondylitis. Clin Biochem 45:541–546PubMedCrossRefGoogle Scholar
  29. 29.
    Yu C, Zhou Y, Miao X et al (2004) Functional haplotypes in the promoter of matrix metalloproteinase-2 predict risk of the occurrence and metastasis of esophageal cancer. Cancer Res 64:7622–7628PubMedCrossRefGoogle Scholar
  30. 30.
    Saracini C, Bolli P, Sticchi E et al (2012) Polymorphisms of genes involved in extracellular matrix remodeling and abdominal aortic aneurysm. J Vasc Surg 55:171–179PubMedCrossRefGoogle Scholar
  31. 31.
    Peng B, Cao L, Ma X et al (2010) Meta-analysis of association between matrix metalloproteinases 2, 7 and 9 promoter polymorphisms and cancer risk. Mutagenesis 25:371–379PubMedCrossRefGoogle Scholar
  32. 32.
    Rodriguez-Lopez J, Perez-Pampin E, Gomez-Reino JJ, Gonzalez A (2006) Regulatory polymorphisms in extracellular matrix protease genes and susceptibility to rheumatoid arthritis: a case–control study. Arthritis Res Ther 8:R1PubMedCrossRefGoogle Scholar
  33. 33.
    Jacq L, Teixeira VH, Garnier S, Petit-Teixeira E, Cornelis F (2008) The MMP2 rs243865-T allele is not a major genetic factor for rheumatoid arthritis in the French Caucasian population. Int J Immunogenet 35:97–99PubMedCrossRefGoogle Scholar
  34. 34.
    Hussein YM, Mohamed RH, Pasha HF, El-Shahawy EE, Alzahrani SS (2011) Association of tumor necrosis factor alpha and its receptor polymorphisms with rheumatoid arthritis in female patients. Cell Immunol 271:192–196PubMedCrossRefGoogle Scholar
  35. 35.
    Yen JH, Chen CJ, Tsai WC et al (2001) Tumor necrosis factor promoter polymorphisms in patients with rheumatoid arthritis in Taiwan. J Rheumatol 28:1788–1792PubMedGoogle Scholar
  36. 36.
    Cvetkovic JT, Wallberg-Jonsson S, Stegmayr B, Rantapaa-Dahlqvist S, Lefvert AK (2002) Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-alpha, IL-1beta, and IL-1Ra genes. J Rheumatol 29:212–219PubMedGoogle Scholar
  37. 37.
    Pawlik A, Florczak M, Ostanek L et al (2005) TNF-alpha −308 promoter polymorphism in patients with rheumatoid arthritis. Scand J Rheumatol 34:22–26PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Rongbin Sun
    • 1
  • Yong Huang
    • 1
  • Hui Zhang
    • 1
  • Ruiping Liu
    • 1
    • 2
  1. 1.Department of Orthopedic TraumaAffiliated Hospital of Nanjing Medical University, Changzhou Second People’s HospitalChangzhouChina
  2. 2.Central LaboratoryAffiliated Hospital of Nanjing Medical University, Changzhou Second People’s HospitalChangzhouChina

Personalised recommendations