Abstract
Interleukin-10 (IL-10) is a pleiotropic cytokine with both immunosuppressive and immunostimulatory functions. Its roles in infections and autoimmunity may have resulted in selective pressures on polymorphisms within the gene, leading to genomic coexistence of several semi-conserved haplotypes involved with diverse pathogen interactions during genomic evolution. Previous studies focused either exclusively on promoter haplotypes or on individual SNPs. We genotyped 21 single nucleotide polymorphisms in the human IL10 gene and examined this variation compared to other mammalian species sequences. Haplotype heterogeneity in human populations is centered around ‘classic’ ‘proximal’ promoter polymorphisms: −592, −819 and −1082. High-producing GCC haplotypes are by far the most numerous and diverse group, the intermediate IL-10 producing ACC-inclusive haplotypes seem to be related most closely to the ancestral haplotype, and the ATA-inclusive haplotypes cluster a separate branch with strong bootstrap support. We looked at associations of corresponding haplotypes with HIV progression. A haplotype trend regression confirmed that individuals carrying the low-producing ATA-inclusive haplotypes in European Americans progress to AIDS faster, and most likely explain the role of IL10. Our findings are consistent with the hypothesis that existing polymorphisms in this gene may reflect a balance of historic adaptive responses to autoimmune, infectious and other disease agents.
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References
UNAIDS. AIDS Epidemic Update. UNAIDS/WHO: Geneva, Switzerland, 2006.
Dumont F . Therapeutic potential of IL-10 and its viral homologues: an update. Expert Opin Ther Patents 2003; 13: 1551–1577.
O’Brien TR, Winkler C, Dean M, Nelson JA, Carrington M, Michael NL et al. HIV-1 infection in a man homozygous for CCR5 delta 32. Lancet 1997; 349: 1219.
Tang J, Penman-Aguilar A, Lobashevsky E, Allen S, Kaslow RA . HLA-DRB1 and -DQB1 alleles and haplotypes in Zambian couples and their associations with heterosexual transmission of HIV type 1. J Infect Dis 2004; 189: 1696–1704.
Shrestha S, Strathdee SA, Galai N, Oleksyk TK, Fallin MD, Mehta S et al. Behavioral risk exposure and host genetics of susceptibility to HIV-1 infection. J Infect Dis 2006; 193: 16–26.
Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA et al. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. Science 1997; 277: 959–965.
Kaslow RA, Dorak T, Tang JJ . Influence of host genetic variation on susceptibility to HIV type 1 infection. J Infect Dis 2005; 191 (Suppl 1): S68–S77.
Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005; 307: 1434–1440.
Telenti A, Goldstein DB . Genomics meets HIV-1. Nat Rev Microbiol 2006; 4: 865–873.
Shin HD, Winkler C, Stephens JC, Bream J, Young H, Goedert JJ et al. Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10. Proc Natl Acad Sci USA 2000; 97: 14467–14472.
Loeuillet C, Deutsch S, Ciuffi A, Robyr D, Taffé P, Muñoz M et al. In vitro whole-genome analysis identifies a susceptibility locus for HIV-1. PLoS Biology 2008; 6: e32.
Nakayama EE, Meyer L, Iwamoto A, Persoz A, Nagai Y, Rouzioux C et al. Protective effect of interleukin-4 -589T polymorphism on human immunodeficiency virus type 1 disease progression: relationship with virus load. J Infect Dis 2002; 185: 1183–1186.
Bream JH, Carrington M, O’Toole S, Dean M, Gerrard B, Shin HD et al. Polymorphisms of the human IFNG gene noncoding regions. Immunogenetics 2000; 51: 50–58.
Donfack J, Buchinsky FJ, Post JC, Ehrlich GD . Human susceptibility to viral infection: the search for HIV-protective alleles among Africans by means of genome-wide studies. AIDS Res Hum Retroviruses 2006; 22: 925–930.
O’Brien SJ, Nelson GW . Human genes that limit AIDS. Nat Genet 2004; 36: 565–574.
Gonzalez E, Dhanda R, Bamshad M, Mummidi S, Geevarghese R, Catano G et al. Global survey of genetic variation in CCR5, RANTES, and MIP-1alpha: impact on the epidemiology of the HIV-1 pandemic. Proc Natl Acad Sci USA 2001; 98: 5199–5204.
Vasilescu A, Heath SC, Ivanova R, Hendel H, Do H, Mazoyer A 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 2003; 4: 441–449.
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.
Ho AS, Moore KW . Interleukin-10 and its receptor. Ther Immunol 1994; 1: 173–185.
Abbas A, Lichtman A, Pober J . Cellular and Molecular Immunology, 2nd edn, W.B. Saunders Company: Philadelphia, 1994.
Beebe AM, Cua DJ, de Waal Malefyt R . The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Cytokine Growth Factor Rev 2002; 13: 403–412.
Llorente L, Zou W, Levy Y, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 1995; 181: 839–844.
Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MB . Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 2006; 12: 1301–1309.
Mocellin S, Marincola F, Riccardo Rossi C, Nitti D, Lise M . The multifaceted relationship between IL-10 and adaptive immunity: putting together the pieces of a puzzle. Cytokine Growth Factor Rev 2004; 15: 61–76.
Hsu DH, de Waal Malefyt R, Fiorentino DF, Dang MN, Vieira P, de Vries J et al. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. Science 1990; 250: 830–832.
Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S . Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci USA 2000; 97: 1695–1700.
Redpath S, Angulo A, Gascoigne NRJ, Ghazal P . Murine cytomegalovirus infection down-regulates MHC Class II expression on macrophages by induction of IL-10. J Immunol 1999; 162: 6701–6707.
Wilson JN, Rockett K, Keating B, Jallow M, Pinder M, Sisay-Joof F et al. A hallmark of balancing selection is present at the promoter region of interleukin 10. Genes Immun 2006; 7: 680–683.
Mormann M, Rieth H, Hua TD, Assohou C, Roupelieva M, Hu SL et al. Mosaics of gene variations in the Interleukin-10 gene promoter affect interleukin-10 production depending on the stimulation used. Genes Immun 2004; 5: 246–255.
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.
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.
Ovcharenko I, Nobrega MA, Loots GG, Stubbs L . ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes. Nucleic Acids Res 2004; 32: W280–W286.
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.
Oleksyk TK, Thio CL, Truelove AL, Goedert JJ, Donfield SM, Kirk GD et al. Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance. Genes Immun 2005; 6: 347–357.
Hilgartner MW, Donfield SM, Willoughby A, Contant Jr CF, Evatt BL, Gomperts ED et al. Hemophilia growth and development study. Design, methods, and entry data. Am J Pediatr Hematol Oncol 1993; 15: 208–218.
Goedert JJ, Kessler CM, Aledort LM, Biggar RJ, Andes WA, White II GC et al. A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med 1989; 321: 1141–1148.
Kaslow RA, Ostrow DG, Detels R, Phair JP, Polk BF, Rinaldo Jr CR . The Multicenter AIDS Cohort Study: rationale, organization, and selected characteristics of the participants. Am J Epidemiol 1987; 126: 310–318.
Reuss E, Fimmers R, Kruger A, Becker C, Rittner C, Hohler T . Differential regulation of interleukin-10 production by genetic and environmental factors—a twin study. Genes Immun 2002; 3: 407–413.
Bandelt HJ, Forster P, Sykes BC, Richards MB . Mitochondrial portraits of human populations using median networks. Genetics 1995; 141: 743–753.
Kundu N, Fulton AM . Interleukin-10 inhibits tumor metastasis, downregulates MHC class I, and enhances NK lysis. Cell Immunol 1997; 180: 55–61.
Moore KW, O’Garra A, de Waal Malefyt R, Vieira P, Mosmann TR . Interleukin-10. Annu Rev Immunol 1993; 11: 165–190.
Wang Y, Rice AP . Interleukin-10 inhibits HIV-1 LTR-directed gene expression in human macrophages through the induction of cyclin T1 proteolysis. Virology 2006; 352: 485–492.
Ji J, Sahu GK, Braciale VL, Cloyd MW . HIV-1 induces IL-10 production in human monocytes via a CD4-independent pathway. Int Immunol 2005; 17: 729–736.
Stylianou E, Aukrust P, Kvale D, Muller F, Froland SS . IL-10 in HIV infection: increasing serum IL-10 levels with disease progression—down-regulatory effect of potent anti-retroviral therapy. Clin Exp Immunol 1999; 116: 115–120.
Akridge RE, Oyafuso LK, Reed SG . IL-10 is induced during HIV-1 infection and is capable of decreasing viral replication in human macrophages. J Immunol 1994; 153: 5782–5789.
Graziosi C, Pantaleo G, Gantt KR, Fortin JP, Demarest JF, Cohen OJ et al. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science 1994; 265: 248–252.
Zanussi S, Simonelli C, D’Andrea M, Caffau C, Clerici M, Tirelli U et al. CD8+ lymphocyte phenotype and cytokine production in long-term non-progressor and in progressor patients with HIV-1 infection. Clin Exp Immunol 1996; 105: 220–224.
Elrefaei M, Barugahare B, Ssali F, Mugyenyi P, Cao H . HIV-specific IL-10-positive CD8+ T cells are increased in advanced disease and are associated with decreased HIV-specific cytolysis. J Immunol 2006; 176: 1274–1280.
Ostrowski MA, Gu JX, Kovacs C, Freedman J, Luscher MA, MacDonald KS . Quantitative and qualitative assessment of human immunodeficiency virus type 1 (HIV-1)-specific CD4+ T cell immunity to gag in HIV-1-infected individuals with differential disease progression: reciprocal interferon-gamma and interleukin-10 responses. J Infect Dis 2001; 184: 1268–1278.
Delves P, Roitt I . Encyclopedia of Immunology, 2nd edn, Academic Press: San Diego, 1998.
Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, Crotty S et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med 2006; 203: 2461–2472.
Wu M-Y, Chen H-F, Chen S-U, Chao K-H, Yang Y-S, Ho H-N . Increase in the production of interleukin-10 early after implantation is related to the success of pregnancy. Am J Reprod Immunol 2001; 46: 386–392.
Westendorp RGJ, van Dunne FM, Kirkwood TBL, Helmerhorst FM, Huizinga TWJ . Optimizing human fertility and survival. Nat Med 2001; 7: 873.
Redpath S, Ghazal P, Gascoigne NRJ . Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol 2001; 9: 86–92.
Woolfe A, Goodson M, Goode DK, Snell P, McEwen GK, Vavouri T et al. Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol 2005; 3: e7.
Smith MW, Patterson N, Lautenberger JA, Truelove AL, McDonald GJ, Waliszewska A et al. A high-density admixture map for disease gene discovery in african americans. Am J Hum Genet 2004; 74: 1001–1013.
Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P et al. Large-scale copy number polymorphism in the human genome. Science 2004; 305: 525–528.
Amundadottir LT, Sulem P, Gudmundsson J, Helgason A, Baker A, Agnarsson BA et al. A common variant associated with prostate cancer in European and African populations. Nat Genet 2006; 38: 652–658.
Vlahov D, Anthony JC, Munoz A, Margolick J, Nelson KE, Celentano DD et al. The ALIVE study, a longitudinal study of HIV-1 infection in intravenous drug users: description of methods and characteristics of participants. NIDA Res Monogr 1991; 109: 75–100.
CDC. Centers for Disease Control: revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992; 41: RR-17.
CDC. Centers for Disease Control: revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR 1987; 36: 1S–15S.
Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R 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.
De La Vega FM, Dailey D, Ziegle J, Williams J, Madden D, Gilbert DA . New generation pharmacogenomic tools: a SNP linkage disequilibrium map, validated SNP assay resource, and high throughput instrumentation system for large scale genetic studies. BioTechniques 2002; 32: S48–S54.
Kumar S, Tamura K, Nei M . MEGA3: integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform 2004; 5: 150–163.
Nei M, Kumar S . Molecular Evolution and Phylogenetics. Oxford University Press: New York, 2000, 352pp.
Posada D, Crandall KA . Intraspecific gene genealogies: trees grafting into networks. Trends Ecol Evol 2001; 16: 37–45.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Schaid DJ . Evaluating associations of haplotypes with traits. Genet Epidemiol 2004; 27: 348–364.
SAS. SAS/Genetics. SAS Institute Inc.: Cary, NC, 2003.
Acknowledgements
We thank the patients and staff of all the participating cohorts in the study. We thank Drs Cheryl Winkler, Michael Dean and Mary Carrington for helpful insights in developing the ideas for this paper. We are also grateful to Bailey Kessing, Michael Malasky and Mary Thompson for their assistance. We thank Maritta Grau and Allen Kane of Scientific Publications, Graphics and Media, SAIC-Frederick Inc., for help with the study preparation. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does it mention of trade names, commercial products, or organizations, which imply the endorsement by the US government. The project included in this paper has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400.
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Oleksyk, T., Shrestha, S., Truelove, A. et al. Extended IL10 haplotypes and their association with HIV progression to AIDS. Genes Immun 10, 309–322 (2009). https://doi.org/10.1038/gene.2009.9
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DOI: https://doi.org/10.1038/gene.2009.9
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