, Volume 59, Issue 3, pp 187–195 | Cite as

Polymorphism in intron 1 of the interferon-gamma gene influences both serum immunoglobulin E levels and the risk for chronic hepatitis B virus infection in Polynesians

  • William AbbottEmail author
  • Edward Gane
  • Ingrid Winship
  • Stephen Munn
  • Colin Tukuitonga
Original Paper


Intron 1 of the interferon-gamma (IFNG) gene contains two polymorphisms. The 12 CA-repeat allele of the +875 IFNGCA microsatellite and the T allele of the +A874T single nucleotide polymorphism (SNP) have been associated with increased in vitro IFNG production and a variety of clinical phenotypes. The purpose of this study was to determine whether these polymorphisms influence total serum IgE levels [tsIgE] and the outcome of a hepatitis B virus (HBV) infection. IFNGCA and +A874T were typed in 186 asthmatics of Niuean ancestry and in Polynesian women with a chronic HBV infection (n = 60) and with natural immunity to the HBV (n = 66). The IFNGCA genotype was associated with [tsIgE] in asthmatic children (n = 51, p = 0.004) but not adults (n = 135, p = 0.87). The data were consistent with a co-dominant influence of the 12 CA-repeat allele on high [tsIgE]. The IFNGCA genotype was also associated with the risk for chronic HBV infection (χ 2 = 11.6, p = 0.003) because of a dominant effect of the 12 CA-repeat allele on developing natural immunity in homozygotes (OR = 5.8, p = 0.003) and heterozygotes (OR = 2.7, p = 0.01). Similar associations were found for the T allele of the +A874T SNP. The possibility that these associations were due to linked alleles in the adjacent 783 bp of the promoter and 3′-untranslated region of the IFNG gene was excluded by direct sequencing. In summary, high-IFNG-producing alleles in intron 1 of the IFNG locus are associated with high [tsIgE] in asthmatic children from Niue and with natural immunity to the HBV in Polynesian women. These findings are consistent with a previous report of an association between +875 IFNGCA and [tsIgE] and provide preliminary evidence of a new association with the outcome of an HBV infection.


Interferon gamma Immunoglobulin E Hepatitis B virus Niue Polynesia 



We would like to thank Malama Nilau for recruiting study subjects from the Niuean community. We would like to thank Liam Williams and Kristine Boxen for technical assistance. We are particularly grateful to the volunteers.

Dr. Abbott was awarded the Harold Thomas Rotary Research Fellowship by the National Child Health Research Foundation to begin this work, which was also supported by the Lloyd Morgan Lions Clubs Charitable Trust New Zealand, the Maurice and Phyllis Paykel Trust, the Auckland Medical Research Foundation and the Auckland Asthma Society. We also wish to acknowledge helpful discussions with Dr. David Duffy and Professor W.O.M. Cookson. All experiments were performed in accordance with the laws of New Zealand.


  1. Abbott WG, Winship IM, Wilsher ML, Nilau M, Tukuitonga CF (2004) Asthma phenotypes in Niue Islanders. Respirology 9:521–527PubMedCrossRefGoogle Scholar
  2. Abbott WG, Winship IM, Gane EJ, Finau SA, Munn SR, Tukuitonga CE (2006) Genetic diversity and linkage disequilibrium in the Polynesian population of Niue Island. Hum Biol 78:131–145PubMedCrossRefGoogle Scholar
  3. Ahn SH, Han KH, Park JY, Lee CK, Kang SW, Chon CY, Kim YS, Park K, Kim DK, Moon YM (2000) Association between hepatitis B virus infection and HLA-DR type in Korea. Hepatology 31:1371–1373PubMedCrossRefGoogle Scholar
  4. Asderakis A, Sankaran D, Dyer P, Johnson RW, Pravica V, Sinnott PJ, Roberts I, Hutchinson IV (2001) Association of polymorphisms in the human interferon-gamma and interleukin-10 gene with acute and chronic kidney transplant outcome: the cytokine effect on transplantation. Transplantation 71:674–677PubMedCrossRefGoogle Scholar
  5. Bazaral M, Orgel HA, Hamburger RN (1971) IgE levels in normal infants and mothers and an inheritance hypothesis. J Immunol 107:794–801PubMedGoogle Scholar
  6. Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, Hill AV (1999) Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 179:721–724PubMedCrossRefGoogle Scholar
  7. Blumenthal MN, Namboodiri K, Mendell N, Gleich G, Elston RC, Yunis E (1981) Genetic transmission of serum IgE Levels. Am J Med Genet 10:219–228PubMedCrossRefGoogle Scholar
  8. Bouzigon E, Chaudru V, Carpentier AS, Dizier MH, Oryszczyn MP, Maccario J, Kauffmann F, Demenais F (2004) Familial correlations and inter-relationships of four asthma-associated quantitative phenotypes in 320 French EGEA families ascertained through asthmatic probands. Eur J Hum Genet 12:955–963PubMedCrossRefGoogle Scholar
  9. Bravo MJ, de Dios Colmenero J, Alonso A, Caballero A (2003) Polymorphisms of the interferon gamma and interleukin 10 genes in human brucellosis. Eur J Immunogenet 30:433–435PubMedCrossRefGoogle Scholar
  10. Bream JH, Ping A, Zhang X, Winkler C, Young HA (2002) A single nucleotide polymorphism in the proximal IFN-gamma promoter alters control of gene transcription. Genes Immun 3:165–169PubMedCrossRefGoogle Scholar
  11. Cabantous S, Poudiougou B, Traore A, Keita M, Cisse MB, Doumbo O, Dessein AJ, Marquet S (2005) Evidence that interferon-gamma plays a protective role during cerebral malaria. J Infect Dis 192:854–860PubMedCrossRefGoogle Scholar
  12. Cavet J, Dickinson AM, Norden J, Taylor PR, Jackson GH, Middleton PG (2001) Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 98:1594–1600PubMedCrossRefGoogle Scholar
  13. Chevillard C, Henri S, Stefani F, Parzy D, Dessein A (2002) Two new polymorphisms in the human interferon gamma (IFN-gamma) promoter. Eur J Immunogenet 29:53–56PubMedCrossRefGoogle Scholar
  14. Cooke GS, Campbell SJ, Sillah J, Gustafson P, Bah B, Sirugo G, Bennett S, McAdam KP, Sow O, Lienhardt C, Hill AV (2006) Polymorphism within the interferon-gamma/receptor complex is associated with pulmonary tuberculosis. Am J Respir Crit Care Med 174:339–343PubMedCrossRefGoogle Scholar
  15. Daher S, Shulzhenko N, Morgun A, Mattar R, Rampim GF, Camano L, DeLima MG (2003) Associations between cytokine gene polymorphisms and recurrent pregnancy loss. J Reprod Immunol 58:69–77PubMedCrossRefGoogle Scholar
  16. Demenais F, Boussaha M, Dizier MH (2002) A polymorphism of intron 1 interferon gamma gene (IFNG) influences immunoglobulin E (IgE) levels in 107 French EGEA families. Genet Epidemiol 23:275–276Google Scholar
  17. Dizier MH, Besse-Schmittler C, Guilloud-Bataille M, Annesi-Maesano I, Boussaha M, Bousquet J, Charpin D, Degioanni A, Gormand F, Grimfeld A, Hochez J, Hyne G, Lockhart A, Luillier-Lacombe M, Matran R, Meunier F, Neukirch F, Pacheco Y, Parent V, Paty E, Pin I, Pison C, Scheinmann P, Thobie N, Vervloet D, Kauffmann F, Feingold J, Lathrop M, Demenais F (2000) Genome screen for asthma and related phenotypes in the French EGEA study. Am J Respir Crit Care Med 162:1812–1818PubMedGoogle Scholar
  18. Etokebe GE, Bulat-Kardum L, Johansen MS, Knezevic J, Balen S, Matakovic-Mileusnic N, Matanic D, Flego V, Pavelic J, Beg-Zec Z, Dembic Z (2006) Interferon-gamma gene (T874A and G2109A) polymorphisms are associated with microscopy-positive tuberculosis. Scand J Immunol 63:136–141PubMedCrossRefGoogle Scholar
  19. Fitness J, Floyd S, Warndorff DK, Sichali L, Malema S, Crampin AC, Fine PE, Hill AV (2004) Large-scale candidate gene study of tuberculosis susceptibility in the Karonga district of northern Malawi. Am J Trop Med Hyg 71:341–349PubMedGoogle Scholar
  20. Gerrard JW, Rao DC, Morton NE (1978) A genetic study of immunoglobulin E. Am J Hum Genet 30:46–58PubMedGoogle Scholar
  21. Goris A, Epplen C, Fiten P, Andersson M, Murru R, Sciacca FL, Ronsse I, Jackel S, Epplen JT, Marrosu MG, Olsson T, Grimaldi LM, Opdenakker G, Billiau A, Vandenbroeck K (1999) Analysis of an IFN-gamma gene (IFNG) polymorphism in multiple sclerosis in Europe: effect of population structure on association with disease. J Interferon Cytokine Res 19:1037–1046PubMedCrossRefGoogle Scholar
  22. Grundbacher FJ (1975) Causes of variation in serum IgE levels in normal populations. J Allergy Clin Immunol 56:104–111PubMedCrossRefGoogle Scholar
  23. Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV (1996) Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 4:25–36PubMedCrossRefGoogle Scholar
  24. Heaton T, Rowe J, Turner S, Aalberse RC, de Klerk N, Suriyaarachchi D, Serralha M, Holt BJ, Hollams E, Yerkovich S, Holt K, Sly PD, Goldblatt J, Le Souef P, Holt PG (2005) An immunoepidemiological approach to asthma: identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children. Lancet 365:142–149PubMedCrossRefGoogle Scholar
  25. Hohler T, Kruger A, Gerken G, Schneider PM, Meyer zum Buschenefelde KH, Rittner C (1998) A tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated with chronic hepatitis B infection. Clin Exp Immunol 111:579–582PubMedCrossRefGoogle Scholar
  26. Hohler T, Reuss E, Adams P, Bartsch B, Weigmann B, Worns M, Galle PR, Victor A, Neurath MF (2005) A genetic basis for IFN-gamma production and T-bet expression in humans. J Immunol 175:5457–5462PubMedGoogle Scholar
  27. Lin TM, Chen CJ, Wu MM, Yang CS, Chen JS, Lin CC, Kwang TY, Hsu ST, Lin SY, Hsu LC (1989) Hepatitis B virus markers in Chinese twins. Anticancer Res 9:737–941PubMedGoogle Scholar
  28. Lio D, Marino V, Serauto A, Gioia V, Scola L, Crivello A, Forte GI, Colonna-Romano G, Candore G, Caruso C (2002) Genotype frequencies of the +874T–>A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis. Eur J Immunogenet 29:371–374PubMedCrossRefGoogle Scholar
  29. Lopez-Maderuelo D, Arnalich F, Serantes R, Gonzalez A, Codoceo R, Madero R, Vazquez JJ, Montiel C (2003) Interferon-gamma and interleukin-10 gene polymorphisms in pulmonary tuberculosis. Am J Respir Crit Care Med 167:970–975PubMedCrossRefGoogle Scholar
  30. Maini MK, Boni C, Ogg GS, King AS, Reignat S, Lee CK, Larrubia JR, Webster GJ, McMichael AJ, Ferrari C, Williams R, Vergani D, Bertoletti A (1999) Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology 117:1386–1396PubMedCrossRefGoogle Scholar
  31. Manly KF (2005) Reliability of statistical associations between genes and disease. Immunogenetics 57:549–558PubMedCrossRefGoogle Scholar
  32. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ (1995) Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 332:133–138PubMedCrossRefGoogle Scholar
  33. Masutani K, Miyake K, Nakashima H, Hirano T, Kubo M, Hirakawa M, Tsuruya K, Fukuda K, Kanai H, Otsuka T, Hirakata H, Iida M (2003) Impact of interferon-gamma and interleukin-4 gene polymorphisms on development and progression of IgA nephropathy in Japanese patients. Am J Kidney Dis 41:371–379PubMedCrossRefGoogle Scholar
  34. Mathias RA, Beaty TH, Bailey-Wilson JE, Bickel C, Stockton ML, Barnes KC (2005) Inheritance of total serum IgE in the isolated Tangier Island from Virginia: complexities associated with genealogical depth of pedigrees in segregation analyses. Hum Hered 59:228–238PubMedCrossRefGoogle Scholar
  35. Meng XQ, Chen HG, Ma YL, Liu KZ (2003) Influence of HLA class II molecules on the outcome of hepatitis B virus infection in population of Zhejiang Province in China. Hepatobiliary Pancreat Dis Int 2:230–233PubMedGoogle Scholar
  36. Milne A, Allwood GK, Moyes CD, Pearce NE, Newell K (1987) A seroepidemiological study of the prevalence of hepatitis B infections in a hyperendemic New Zealand community. Int J Epidemiol 16:84–90PubMedCrossRefGoogle Scholar
  37. Nagarkatti R, Rao BC, Rishi JP, Chetiwal R, Shandilya V, Vijayan V, Kumar R, Pemde HK, Sharma SK, Sharma S, Singh AB, Gangal SV, Ghosh B (2002) Association of IFNG gene polymorphism with asthma in the Indian population. J Allergy Clin Immunol 110:410–412PubMedCrossRefGoogle Scholar
  38. Palmer LJ, Burton PR, James AL, Musk AW, Cookson WO (2000) Familial aggregation and heritability of asthma-associated quantitative traits in a population-based sample of nuclear families. Eur J Hum Genet 8:853–860PubMedCrossRefGoogle Scholar
  39. Palmer LJ, Cookson WO, James AL, Musk AW, Burton PR (2001) Gibbs sampling-based segregation analysis of asthma-associated quantitative traits in a population-based sample of nuclear families. Genet Epidemiol 20:356–372PubMedCrossRefGoogle Scholar
  40. Pravica V, Asderakis A, Perrey C, Hajeer A, Sinnott PJ, Hutchinson IV (1999) In vitro production of IFN-gamma correlates with CA repeat polymorphism in the human IFN-gamma gene. Eur J Immunogenet 26:1–3PubMedCrossRefGoogle Scholar
  41. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV (2000) A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 61:863–866PubMedCrossRefGoogle Scholar
  42. Prigoshin N, Tambutti M, Larriba J, Gogorza S, Testa R (2004) Cytokine gene polymorphisms in recurrent pregnancy loss of unknown cause. Am J Reprod Immunol 52:36–41PubMedCrossRefGoogle Scholar
  43. Rossol S, Marinos G, Carucci P, Singer MV, Williams R, Naoumov NV (1997) Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B. J Clin Invest 99:3025–3033PubMedCrossRefGoogle Scholar
  44. Rossouw M, Nel HJ, Cooke GS, van Helden PD, Hoal EG (2003) Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Lancet 361:1871–1872PubMedCrossRefGoogle Scholar
  45. Sampogna F, Demenais F, Hochez J, Oryszczyn MP, Maccario J, Kauffmann F, Feingold J, Dizier MH (2000) Segregation analysis of IgE levels in 335 French families (EGEA) using different strategies to correct for the ascertainment through a correlated trait (asthma). Genet Epidemiol 18:128–142PubMedCrossRefGoogle Scholar
  46. Schneider S, Roessli D, Excoffier L (2000) Arlequin ver. 2.000: a software for population genetics data analysis. Genetics and Biometry Laboratory, University of Geneva, SwitzerlandGoogle Scholar
  47. SeattleSNPs (2001) NHLBI program for genomic applications. UW-FHCRC, Seattle, WAGoogle Scholar
  48. Smart JM, Tang ML, Kemp AS (2002) Polyclonal and allergen-induced cytokine responses in children with elevated immunoglobulin E but no atopic disease. Clin Exp Allergy 32:1552–1557PubMedCrossRefGoogle Scholar
  49. Spriewald BM, Witzke O, Wassmuth R, Wenzel RR, Arnold ML, Philipp T, Kalden JR (2005) Distinct tumour necrosis factor alpha, interferon gamma, interleukin 10, and cytotoxic T cell antigen 4 gene polymorphisms in disease occurrence and end stage renal disease in Wegener’s granulomatosis. Ann Rheum Dis 64:457–461PubMedCrossRefGoogle Scholar
  50. Thio CL, Thomas DL, Karacki P, Gao X, Marti D, Kaslow RA, Goedert JJ, Hilgartner M, Strathdee SA, Duggal P, O’Brien SJ, Astemborski J, Carrington M (2003) Comprehensive analysis of class I and class II HLA antigens and chronic hepatitis B virus infection. J Virol 77:12083–12087PubMedCrossRefGoogle Scholar
  51. Thursz MR, Kwiatkowski D, Allsopp CE, Greenwood BM, Thomas HC, Hill AV (1995) Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N Engl J Med 332:1065–1069PubMedCrossRefGoogle Scholar
  52. Tso HW, Ip WK, Chong WP, Tam CM, Chiang AK, Lau YL (2005) Association of interferon gamma and interleukin 10 genes with tuberculosis in Hong Kong Chinese. Genes Immun 6:358–363PubMedCrossRefGoogle Scholar
  53. Vandenbroeck K, Cunningham S, Goris A, Alloza I, Heggarty S, Graham C, Bell A, Rooney M (2003) Polymorphisms in the interferon-gamma/interleukin-26 gene region contribute to sex bias in susceptibility to rheumatoid arthritis. Arthritis Rheum 48:2773–2778PubMedCrossRefGoogle Scholar
  54. Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N (2004) Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 96:434–442PubMedCrossRefGoogle Scholar
  55. Wainwright RB, McMahon BJ, Bender TR, Heyward WL, Nakanishi S, Wainwright KY, Foliaki S, Erickson SL, Fields HA (1986) Prevalence of hepatitis B virus infection in Tonga: identifying high risk groups for immunization with hepatitis B vaccine. Int J Epidemiol 15:567–571PubMedCrossRefGoogle Scholar
  56. Williamson HG, Gust ID, Dimitrakakis M, Liu SQ, Taylor R, Whitmore J, Nemaia HT, Nemaia J (1985) Serological markers of hepatitis B infection in Niue children. N Z Med J 98:275–277PubMedGoogle Scholar
  57. Wright TL (2006) Introduction to chronic hepatitis B infection. Am J Gastroenterol 101(Suppl 1):S1–S6PubMedCrossRefGoogle Scholar
  58. Xu J, Postma DS, Howard TD, Koppelman GH, Zheng SL, Stine OC, Bleecker ER, Meyers DA (2000) Major genes regulating total serum immunoglobulin E levels in families with asthma. Am J Hum Genet 67:1163–1173PubMedCrossRefGoogle Scholar
  59. Zondervan KT, Cardon LR (2004) The complex interplay among factors that influence allelic association. Nat Rev Genet 5:89–100PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • William Abbott
    • 1
    Email author
  • Edward Gane
    • 1
  • Ingrid Winship
    • 3
  • Stephen Munn
    • 1
  • Colin Tukuitonga
    • 2
  1. 1.New Zealand Liver Transplant UnitAuckland City HospitalAucklandNew Zealand
  2. 2.School of Population Health, Tamaki CampusUniversity of AucklandAucklandNew Zealand
  3. 3.Genetic Health Services Victoria, 10th FloorRoyal Children’s HospitalParkvilleAustralia

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