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:

Genomic analysis of Th1–Th2 cytokine genes in an AIDS cohort: identification of IL4 and IL10 haplotypes associated with the disease progression

Abstract

Polymorphisms of Th1–Th2 cytokine genes have previously been implicated in the rate of progression to AIDS in seropositive patients. To evaluate further the impact of these genes in the development of AIDS, we have performed an extensive genetic analysis of IL2, IL4, IL6, IL10, IL12p35 and p40, IL13 and IFNγ. The coding regions and promoters of these genes were sequenced in a Caucasian cohort of 337 HIV-1 seropositive extreme patients (the GRIV cohort) consisting of patients with slow progression and rapid progression, and up to 470 healthy controls. In all, 64 single nucleotide polymorphisms (SNPs) and four deleterious polymorphisms with frequency >1% were identified and evaluated for their association with disease. Statistically significant associations were observed with haplotypes of the IL4 and IL10 genes, but no relation was found with variants of other genes. The catalogue of SNP and haplotypes presented here will facilitate further genetic investigations of Th1–Th2 cytokines in AIDS and other immune-related disorders.

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

Access options

Buy this article

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. O'Shea JJ, Ma A, Lipsky P . Cytokines and autoimmunity. Nat Rev Immunol 2002; 2: 37–45.

    Article  CAS  PubMed  Google Scholar 

  2. Bidwell J, Keen L, Gallagher G et al. Cytokine gene polymorphism in human disease: on-line databases, supplement 1. Genes Immun 2001; 2: 61–70.

    CAS  PubMed  Google Scholar 

  3. Hill AV . Immunogenetics and genomics. Lancet 2001; 357: 2037–2041.

    Article  CAS  PubMed  Google Scholar 

  4. Gibson AW, Edberg JC, Wu J et al. Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhances the risk for systemic lupus erythematosus. J Immunol 2001; 166: 3915–3922.

    Article  CAS  PubMed  Google Scholar 

  5. Lee JY, Goldman D, Piliero LM, Petri M, Sullivan KE . IFN-gamma polymorphisms in systemic lupus erythematosus. Genes Immun 2001; 2: 254–257.

    Article  CAS  PubMed  Google Scholar 

  6. Khani-Hanjani A, Lacaille D, Hoar D et al. Association between dinucleotide repeat in non-coding region of interferon-gamma gene and susceptibility to, and severity of rheumatoid arthritis. Lancet 2000; 356: 820–825.

    Article  CAS  PubMed  Google Scholar 

  7. Constantin A, Navaux F, Lauwers-Cances V et al. Interferon-gamma gene polymorphism and susceptibility to, and severity of rheumatoid arthritis. Lancet 2001; 358: 2051–2052.

    Article  CAS  PubMed  Google Scholar 

  8. Morahan G, Huang D, Ymer SI et al. Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Nat Genet 2001; 27: 218–221.

    Article  CAS  PubMed  Google Scholar 

  9. Dahlman I, Eaves IA, Kosoy R et al. Parameters for reliable results in genetic association studies in common diseases. Nat Genet 2002; 30: 149–150.

    Article  CAS  PubMed  Google Scholar 

  10. Fisher AG, Collalti E, Ratner L, Gallo RC, Wong-Staal F . A molecular clone of HTLV-III with biological activity. Nature 1985; 316: 262–265.

    Article  CAS  PubMed  Google Scholar 

  11. Sodroski J, Goh WC, Rosen C, Campbell K, Haseltine WA . Role of the HTLV-III/LAV envelope in syncitium formation and cytopathicity. Nature 1986; 322: 470–474.

    Article  CAS  PubMed  Google Scholar 

  12. Golding H, Robey FA, Gates III FT et al. Identification of homologous regions in human immunodeficiency virus 1 gp41 and human MHC class II beta 1 domain 1. Monoclonal antibodies against gp41-derived peptide and patients' sera react with native HLA class II antigens, suggesting a role for autoimmunity in the pathogenesis of AIDS. J Exp Med 1988; 167: 914–923.

    Article  CAS  PubMed  Google Scholar 

  13. Ameisen JC, Capron A . Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. Immunol Today 1991; 12: 102–105.

    Article  CAS  PubMed  Google Scholar 

  14. Imberti L, Sottini A, Bettinardi A, Puoti M, Primi D . Selective depletion in HIV infection of T cells that bear specific T cell receptor V beta sequences. Science 1991; 254, 860–862.

    Article  CAS  PubMed  Google Scholar 

  15. Clerici M, Shearer GM . A Th1 to Th2 switch is a critical step in the etiology of HIV infection. Immunol Today 1993; 14: 107–111.

    Article  CAS  PubMed  Google Scholar 

  16. O'Brien SJ, Moore JP . The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. Immunol Rev 2000; 177: 99–111.

    Article  CAS  PubMed  Google Scholar 

  17. Al Jabri AA . HLA and in vitro susceptibility to HIV infection. Mol Immunol 2002; 38: 959–967.

    Article  CAS  PubMed  Google Scholar 

  18. Shin HD, Winkler C, Stephens JC et al. Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10. Proc Natl Acad Sci USA 2000; 97: 14467–14472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nakayama EE, Meyer L, Iwamoto A et al. Protective effect of IL-4–589T polymorphism on HIV-1 disease progression: relationship with viral load. J Infect Dis 2002; 185: 1183–1186.

    Article  CAS  PubMed  Google Scholar 

  20. Bream JH, Carrington M, O'Toole S et al. Polymorphisms of the human IFNG noncoding regions. Immunogenetics 2000; 51: 50–58.

    Article  CAS  PubMed  Google Scholar 

  21. Nakashima H, Miyake K, Inoue Y et al. Association between IL-4 genotype and IL-4 production in the Japanese population. Genes Immun 2002; 3: 107–109.

    Article  CAS  PubMed  Google Scholar 

  22. O'Brien SJ, Nelson GW, Winkler CA, Smith MW . Polygenic and multifactorial disease gene association in man: lessons from AIDS. Annu Rev Genet 2000; 34: 563–591.

    Article  CAS  PubMed  Google Scholar 

  23. Rappaport J, Cho YY, Hendel H et al. 32 bp CCR-5 gene deletion and resistance to fast progression in HIV-1 infected heterozygous. Lancet 1997; 349: 922–923.

    Article  CAS  PubMed  Google Scholar 

  24. Hendel H, Henon N, Lebuanec H et al. Distinctive effects of CCR5, CCR2 and SDF1 genetic polymorphisms on AIDS progression. J AIDS 1998; 19: 381–386.

    CAS  Google Scholar 

  25. Hendel H, Caillat-Zucman S, Lebuanec H et al. New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS. J Immunol 1999; 162: 6942–6946.

    CAS  PubMed  Google Scholar 

  26. John S, Turner D, Donn R et al. Two novel biallelic polymorphisms in the IL-2 gene. Eur J Immunogenet 1998; 25: 419–420.

    Article  CAS  PubMed  Google Scholar 

  27. Hoffmann SC, Stanley EM, Darrin Cox E et al. Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes. Transplant 2001; 72: 1444–1450.

    Article  CAS  Google Scholar 

  28. Rosenwasser LJ, Klemm DJ, Dresback JK et al. Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy 1995; 2: 74–78.

    Article  Google Scholar 

  29. Takabayashi A, Ihara K, Sasaki Y et al. Novel polymorphism in the 5′-untranslated region of the interleukin-4 gene. J Hum Genet 1999; 44: 352–353.

    Article  CAS  PubMed  Google Scholar 

  30. Osiri M, McNicholl J, Moreland LW, Bridges Jr SL . A novel single nucleotide polymorphism and five probable haplotypes in the 5′ flanking region of the IL-6 gene in African Americans. Genes Immun 1999; 1: 166–167.

    Article  CAS  PubMed  Google Scholar 

  31. Fishman D, Faulds G, Jeffery R et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998; 102: 1369–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Turner DM, Williams DM, Sankaran D et al. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997; 24: 1–8.

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. Donger C, Georges JL, Nicaud V et al. New polymorphisms in the IL-10 gene — relationships to myocardial infarction. Eur J Clin Invest 2001; 31: 9–14.

    Article  CAS  PubMed  Google Scholar 

  35. Huang D, Cancilla MR, Morahan G . Complete primary structure, chromosomal localisation, and definition of polymorphisms of the gene encoding the human interleukin-12 p40 subunit. Genes Immun 2000; 1: 515–520.

    Article  CAS  PubMed  Google Scholar 

  36. Hall MA, McGlinn E, Coakley G et al. Genetic polymorphism of IL-12 p40 gene in immune-mediated disease. Genes Immun 2000; 1: 219–224.

    Article  CAS  PubMed  Google Scholar 

  37. Graves PE, Kabesch M, Halonen M et al. A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children. J Allergy Clin Immunol 2000; 105: 506–513.

    Article  CAS  PubMed  Google Scholar 

  38. van der Pouw Kraan TC, van Veen A, Boeije LC et al. An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun 1999; 1: 61–65.

    Article  CAS  PubMed  Google Scholar 

  39. Awata T, Matsumoto C, Urakami T et al. Association of polymorphism in the interferon gamma gene with IDDM. Diabetologia 1994; 37: 1159–1162.

    Article  CAS  PubMed  Google Scholar 

  40. Wu S, Muhleman D, Comings DE . G5644A polymorphism in the interferon-gamma (INFG) gene. Psychiatr Genet 1998; 8: 57.

    Article  CAS  PubMed  Google Scholar 

  41. Wang DG, Fan JB, Siao CJ et al. Large-scale identification, mapping, and genotyping of SNPs in the human genome. Science 1998; 280: 1077–1082.

    Article  CAS  PubMed  Google Scholar 

  42. Cargill M, Altshuler D, Ireland J et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 1999; 22: 231–238.

    Article  CAS  PubMed  Google Scholar 

  43. 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 

  44. Dean M, Carrington M, Winkler C et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 1996; 273:1856–1862.

    Article  CAS  PubMed  Google Scholar 

  45. Valentin A, Lu W, Rosati M et al. Dual effect of interleukin-4 on HIV-1 expression: implications for phenotypic switch and disease progression. Proc Natl Acad Sci USA 1998; 95: 8886–8891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Montaner LJ, Griffin P, Gordon S . Interleukin-10 inhibits initial reverse transcription of human immunodeficiency virus type 1 and mediates a virostatic latent state in primary blood-derived human macrophages in vitro. J Gen Virol 1994; 75: 3393–3400.

    Article  CAS  PubMed  Google Scholar 

  47. Weissman D, Poli G, Fauci AS . Interleukin 10 blocks HIV replication in macrophages by inhibiting the autocrine loop of tumor necrosis factor alpha and interleukin 6 induction of virus. AIDS Res Hum Retroviruses 1994; 10: 1199–1206.

    Article  CAS  PubMed  Google Scholar 

  48. Kollmann TR, Pettoello-Mantovani M, Katopodis NF et al. Inhibition of acute in vivo human immunodeficiency virus infection by human interleukin 10 treatment of SCID mice implanted with human fetal thymus and liver. Proc Natl Acad Sci USA 1996; 93: 3126–3131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Takahashi M, Matsuda F, Margetic N, Lathrop M . Automated identification of single nucleotide polymorphisms from sequencing data. J Bioinf Computat Biol Proc. IEEE CS Bioinformatics Conference 2002, pp 87–96.

  50. Laird N . Handbook of Statistics Vol. 9, Computational Statistic: the EM algorithm. Elsevier Science Publishers BV: Amsterdam, 1993, pp 509–520.

    Google Scholar 

Download references

Acknowledgements

We are grateful to all the patients and all the medical staff who have generously collaborated with the GRIV project. We also thank the EGEA cooperative group for having given access to data on the EGEA (Epidemiological study on the Genetics and Environment of Asthma) study, which was partly supported by an INSERM/MSD convention. The GRIV project is supported by grants from ANRS (Agence Nationale de Recherche sur le SIDA) and ACV (AIDS-Cancer Vaccine Development Foundation). The CNG is supported by the Ministere de la Recherche et des Nouvelles Technologies.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J-F Zagury.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vasilescu, A., Heath, S., Ivanova, R. et al. Genomic analysis of Th1–Th2 cytokine genes in an AIDS cohort: identification of IL4 and IL10 haplotypes associated with the disease progression. Genes Immun 4, 441–449 (2003). https://doi.org/10.1038/sj.gene.6363983

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6363983

Keywords

This article is cited by

Search

Quick links