Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus

Genes & Immunity volume 5, pages 484–492 (2004)Cite this article

Abstract

Several lines of evidence suggest interleukin-10 gene (IL-10) is a candidate gene in susceptibility to systemic lupus erythematosus (SLE). We investigated the association of IL-10 promoter single-nucleotide polymorphisms (SNPs) (−3575T/A, −2849G/A, −2763C/A, −1082A/G, −819T/C and −592A/C) and microsatellites (IL10.R, IL10.G) with SLE in 554 Hong Kong Chinese patients and 708 ethnically matched controls. Six haplotypes (hts) were identified from the SNPs. The genotype distribution of the ht1 (T-C-A-T-A), which is associated with low IL-10 production, was different in patients and controls (P=0.009). The homozygous genotype of non-ht1 was significantly increased in patients (P=0.009, odds ratio (OR)=1.80, 95% CI: 1.15–2.82). The frequency of IL10.G4 of IL10.G was also significantly increased in patients (P=0.017, OR=2.53, 95% CI: 1.18–5.40). We found that the homozygous non-ht1 combined with short allele (CA repeat number ⩽21) of IL10.G has a dose-dependent effect on SLE susceptibility: non-ht1/non-ht1 with homozygous short allele showed a higher OR (OR=4.11, 95% CI: 1.27–13.2, P=0.018) of association with SLE than the genotype of non-ht1/non-ht1 with heterozygous short/long allele (OR=2.98, 95% CI: 1.26–7.07, P=0.013) and homozygous long allele (OR=1.05, 95% CI: 0.62–1.78, P=0.848). The frequency of non-ht1 was significantly increased in patients with serositis (P<0.0001, OR=2.42, 95% CI: 1.55–3.80). In conclusion, the high expression promoter genotype is associated with SLE in Chinese.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Shlomchik MJ, Craft JE, Mamula MJ . From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 2001; 1: 147–153.

    Article  CAS  PubMed  Google Scholar 

  2. Deapen D, Escalante A, Weinrib L et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 1992; 35: 311–318.

    Article  CAS  PubMed  Google Scholar 

  3. Lawrence JS, Martins CL, Drake GL . A family survey of lupus erythematosus. 1. Heritability. J Rheumatol 1987; 14: 867–869.

    Google Scholar 

  4. Vyse TJ, Kotzin BL . Genetic basis of systemic lupus erythematosus. Curr Opin Immunol 1996; 8: 843–851.

    Article  CAS  PubMed  Google Scholar 

  5. Morel L, Rudofsky UH, Longmate JA, Schiffenbauer J, Wakeland EK . Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1994; 1: 219–229.

    Article  CAS  PubMed  Google Scholar 

  6. Wakeland EK, Wandstrat AE, Liu K, Morel L . Genetic dissection of systemic lupus erythematosus. Curr Opin Immunol 1999; 11: 701–707.

    Article  CAS  PubMed  Google Scholar 

  7. Kelly JA, Moser KL, Harley JB . The genetics of systemic lupus erythematosus: putting the pieces together. Genes Immun 2002; 3 (Suppl 1): S71–S85.

    Article  CAS  PubMed  Google Scholar 

  8. Hawkins BR, Wong KL, Wong RWS, Chan KH, Dunckley H, Serjeantson SW . Strong association between the major histocompatibility complex and systemic lupus erythematosus in Southern Chinese. J Rheumatol 1987; 14: 1128–1131.

    CAS  PubMed  Google Scholar 

  9. Lau YL, Lau CS, Chan SY, Karlberg J, Turner MW . Mannose-binding protein in Chinese patients with systemic lupus erythematosus. Arthritis Rheum 1996; 39: 706–708.

    Article  CAS  PubMed  Google Scholar 

  10. Ip WK, Chan SY, Lau CS, Lau YL . Association of systemic lupus erythematosus with promoter polymorphisms of the mannose-binding lectin gene. Arthritis Rheum 1998; 41: 1663–1668.

    CAS  PubMed  Google Scholar 

  11. Ratnoff WD . Inherited deficiencies of complement in rheumatic diseases. Rheum Dis Clin N Am 1996; 22: 75–94.

    Article  CAS  Google Scholar 

  12. Duits AJ, Bootsma H, Derksen RH et al. Skewed distribution of IgG Fc receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum 1995; 39: 1832–1836.

    Article  Google Scholar 

  13. Wilson AG, Gordon C, diGiovine FS et al. A genetic association between systemic lupus erythematosus and tumor necrosis factor alpha. Eur J Immunol 1994; 24: 191–195.

    Article  CAS  PubMed  Google Scholar 

  14. Prokunina L, Castillejo-Lopez C, Oberg F et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002; 32: 666–669.

    Article  CAS  PubMed  Google Scholar 

  15. Gaffney PM, Kearns GM, Shark KB et al. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci USA 1998; 95: 14875–14879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gaffney PM, Ortmann WA, Selby SA et al. Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analysis of 187 sib-pair families. Am J Hum Genet 2000; 66: 547–556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gray-McGuire C, Moser KL, Gaffney PM et al. Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16–15.2. Am J Hum Genet 2000; 67: 1460–1469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lindqvist AK, Steinsson K, Johanneson B et al. A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. J Autoimmun 2000; 14: 169–178.

    Article  CAS  PubMed  Google Scholar 

  19. Shai R, Quismorio Jr FP, LI L et al. Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 1999; 8: 639–644.

    Article  CAS  PubMed  Google Scholar 

  20. Moser KL, Neas BR, Salmon JE et al. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci USA 1998; 95: 14869–14874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Johanneson B, Lima G, von Salome J et al. A major susceptibility locus for systemic lupus erythemathosus maps to chromosome 1q31. Am J Hum Genet. 2002; 71: 1060–1071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lander ES, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.

    Article  CAS  PubMed  Google Scholar 

  23. Tsao BP, Cantor RM, Kalunian KC et al. Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J Clin Invest 1997; 99: 725–731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fiorentino DF, Bond MW, Mosmann TR . Two types of mouse T helper cell IV. Th2 clones secrete a factor that inhibits cytokine production. J Exp Med 1989; 170: 2081–2095.

    Article  CAS  PubMed  Google Scholar 

  25. Taga K, Tosato G . IL-10 inhibits T cell proliferation and IL-2 production. J Immunol 1992; 148: 1143–1148.

    CAS  PubMed  Google Scholar 

  26. Ding L, Linsley PS, Huang LY, Germain RN, Shevach EM . IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up regulation of B7 expression. J Immunol 1993; 151: 1224–1234.

    CAS  PubMed  Google Scholar 

  27. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A . Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19: 683–765.

    Article  CAS  PubMed  Google Scholar 

  28. Llorente L, Richaud-Patin Y, Wijdenes J et al. Spontaneous production of interleukin-10 by B lymphocytes and monocytes in systemic lupus erythematosus. Eur Cytokine Network 1993; 4: 421–427.

    CAS  Google Scholar 

  29. Grondal G, Gunnarsson I, Ronnelid J, Rogberg S, Klareskog L, Lundberg I . Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin Exp Rheumatol 2000; 18: 565–570.

    CAS  PubMed  Google Scholar 

  30. Llorente L, Richaud-patin Y, Couderc J et al. Dysregulation of interleukin-10 production in relatives of patients with systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1429–1435.

    Article  CAS  PubMed  Google Scholar 

  31. Ishida H, Muchamuel T, Sakaguchi S, Andrade S, Menon S, Howard M . Continuous adminstration of anti-interleukin 10 antibodies delays the onset of autoimmunity in NZB/W F1 mice. J Exp Med 1994; 179: 305–310.

    Article  CAS  PubMed  Google Scholar 

  32. Westendorp RG, Langermans JA, Huizinga TW et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997; 349: 170–173.

    Article  CAS  PubMed  Google Scholar 

  33. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV . An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997; 24: 1–8.

    Article  CAS  PubMed  Google Scholar 

  34. Eskdale J, Keijsers V, Huizinga T, Gallagher G . Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL-10) locus. Genes Immun 1999; 1: 151–155.

    Article  CAS  PubMed  Google Scholar 

  35. D'Alfonso S, Rampi M, Rolando V, Giordano M, Momigliano-Richiardi P . New polymorphisms in the IL-10 promoter region. Genes Immun 2000; 1: 231–233.

    Article  CAS  PubMed  Google Scholar 

  36. Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP . Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 2001; 166: 3915–3922.

    Article  CAS  PubMed  Google Scholar 

  37. Lazarus M, Hajeer AH, Turner D et al. Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol 1997; 24: 2314–2317.

    CAS  PubMed  Google Scholar 

  38. Kube D, Platzer C, von Knethen A et al. Isolation of the human IL 10 promoter: characterization of the promoter activity in Burkitt's lymphoma cell lines. Cytokine 1995; 7: 1–7.

    Article  CAS  PubMed  Google Scholar 

  39. Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE . Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology 1999; 30: 526–530.

    Article  CAS  PubMed  Google Scholar 

  40. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P . Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 1999; 42: 1101–1108.

    Article  CAS  PubMed  Google Scholar 

  41. Eskdale J, Gallagher G . A polymorphic dinucleotide repeat in the human IL-10 promoter. Immunogenetics 1995; 42: 444–445.

    Article  CAS  PubMed  Google Scholar 

  42. Eskdale J, Kube D, Gallagher G . A second polymorphic diuncleotide repeat in the 5′ flanking region of the human IL-10 gene. Immunogenetics 1996; 45: 82–83.

    Article  CAS  PubMed  Google Scholar 

  43. Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW . Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA 1998; 95: 9465–9470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mok CC, Lanchbury JS, Chan DW, Lau CS . Interleukin-10 promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum 1998; 41: 1090–1095.

    Article  CAS  PubMed  Google Scholar 

  45. Long JC, Williams RC, Urbanek M . An E–M algorithm and testing strategy for multiple-locus haplotypes. Am J Hum Genet 1995; 56: 799–810.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. D'Alfonso S, Giordano M, Mellai M et al. Association tests with systemic lupus erythematosus (SLE) of IL10 markers indicate a direct involvement of a CA repeat in the 5′ regulatory region. Genes Immun 2002; 3: 454–463.

    Article  CAS  PubMed  Google Scholar 

  47. Eskdale J, Wordsworth P, Bowman S, Field M, Gallagher G . Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus. Tissue Antigens 1997; 49: 635–639.

    Article  CAS  PubMed  Google Scholar 

  48. Mehrian R, Quismorio Jr FP, Strassmann G et al. Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus. Arthritis Rheum 1998; 41: 596–602.

    Article  CAS  PubMed  Google Scholar 

  49. D'Alfonso S, Rampi M, Bocchio D, Colombo G, Scorza-Smeraldi R, Momigliano-Richiardi P . Systemic lupus erythematosus candidate genes in the Italian population; evidence for a significant association with interleukin-10. Arthritis Rheum 2000; 43: 120–128.

    Article  CAS  PubMed  Google Scholar 

  50. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN . Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33: 177–182.

    Article  CAS  PubMed  Google Scholar 

  51. Colhoun HM, McKeigue PM, Davey Smith G . Problems of reporting genetic associations with complex outcomes. Lancet 2003; 361: 865–872.

    Article  PubMed  Google Scholar 

  52. Temple SE, Lim E, Cheong KY et al. Alleles carried at positions −819 and −592 of the IL10 promoter affect transcription following stimulation of peripheral blood cells with Streptococcus pneumoniae. Immunogenetics 2003; 55: 629–632.

    Article  CAS  PubMed  Google Scholar 

  53. Padyukov, Hahn-Zoric M, Lau YL, Hanson LA . Different allelic frequencies of several cytokine genes in Hong Kong Chinese and Swedish Caucasians. Genes Immun 2001; 2: 280–283.

    Article  CAS  PubMed  Google Scholar 

  54. Moraes MO, Santos AR, Schonkeren JJ et al. Interleukin-10 promoter haplotypes are differently distributed in the Brazilian vs the Dutch population. Immunogenetics 2003; 54: 896–899.

    CAS  PubMed  Google Scholar 

  55. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–1277.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was partially supported by the Edward Sai-Kim Hotung Pediatric Education and Research Fund (#38) and Outstanding Researcher Award (YLL) of The University of Hong Kong.

Author information

Author notes

  1. The authors do not have commercial or other associations that might pose a conflict of interest

Authors and Affiliations

  1. Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, SAR, China

    W P Chong, W K Ip, W H-S Wong & Y L Lau

  2. Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, SAR, China

    C S Lau & T M Chan

Authors
  1. W P Chong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W K Ip
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W H-S Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C S Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T M Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y L Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y L Lau.

Additional information

The present study was approved by the Ethics Committee of the Faculty of Medicine, The University of Hong Kong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chong, W., Ip, W., Wong, WS. et al. Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus. Genes Immun 5, 484–492 (2004). https://doi.org/10.1038/sj.gene.6364119

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364119

Keywords

This article is cited by

Search

Advanced search

Quick links