- Research article
- Open Access
- Open Peer Review
The interferon gamma gene polymorphism +874 A/T is associated with severe acute respiratory syndrome
- Wai Po Chong†1,
- WK Eddie Ip†1,
- Gloria Hoi Wan Tso1,
- Man Wai Ng1,
- Wilfred Hing Sang Wong1,
- Helen Ka Wai Law1,
- Raymond WH Yung2,
- Eudora Y Chow3,
- KL Au4,
- Eric YT Chan5,
- Wilina Lim6,
- JS Malik Peiris7 and
- Yu Lung Lau1Email author
© Po Chong et al; licensee BioMed Central Ltd. 2006
- Received: 07 February 2006
- Accepted: 04 May 2006
- Published: 04 May 2006
Cytokines play important roles in antiviral action. We examined whether polymorphisms of IFN-γ,TNF-α and IL-10 affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS).
A case-control study was carried out in 476 Chinese SARS patients and 449 healthy controls. We tested the polymorphisms of IFN-γ,TNF-α and IL-10 for their associations with SARS.
IFN-γ +874A allele was associated with susceptibility to SARS in a dose-dependent manner (P < 0.001). Individuals with IFN-γ +874 AA and AT genotype had a 5.19-fold (95% Confidence Interval [CI], 2.78-9.68) and 2.57-fold (95% CI, 1.35-4.88) increased risk of developing SARS respectively. The polymorphisms of IL-10 and TNF-α were not associated with SARS susceptibility.
IFN-γ +874A allele was shown to be a risk factor in SARS susceptibility.
- Severe Acute Respiratory Syndrome
- Antiviral Response
- Severe Acute Respiratory Syndrome
- Severe Acute Respiratory Syndrome Patient
- Severe Acute Respiratory Syndrome Coronavirus
Severe acute respiratory syndrome (SARS) is an infectious disease caused by SARS coronavirus  with >8000 cases and 774 deaths reported in 2003 . Much progress has been made in understanding SARS coronavirus but the pathogenesis is still unclear . It was reported that old age, diabetes mellitus and heart disease were risk factors for adverse prognosis of SARS [4–6], however, little is known about the contribution of genetic factors. We have demonstrated that genetic haplotypes associated with low serum mannose-binding lectin (MBL) were associated with SARS  and our findings were recently replicated . Recently, homozygotes for CLEC4M tandem repeats were reported to be less susceptible to SARS in Hong Kong Chinese .
Cytokines are known to be important in antiviral action. Interferon (IFN)-γ from T and natural killer (NK) cells is important in driving the T helper cell type 1 (Th1) responses. It also activates monocytes and macrophages, which in turn take part in antiviral responses by producing free radicals and pro-inflammatory cytokines like tumor necrosis factor (TNF)-α. . TNF-α then regulates expression of neutrophil-endothelial cell adhesion molecules and chemokines, which recruit leukocytes to the site of infection [11–13]. Thus, IFN-γand TNF-α play important role in antiviral response and inflammation.
Interleukin 10 (IL-10) is an antiinflammatory cytokine that inhibits the activation and effector function of Th1 cells, monocytes, and macrophages . IL-10 appears to limit and ultimately terminate inflammatory responses by blocking the expression of a number of pro-inflammatory cytokines and chemokines . In animal model, IL10 counteracts the inflammatory response by inhibiting TNF-α production and neutrophil activation, and leads to a reduction of the lung tissue injury . Thus, IL-10 plays an important role in regulating many immune and inflammatory processes. Various studies showed that a high IL-10 level would result in suppression of innate host defense and lead to increasing susceptibility of the host to various microbes and death [17–19].
Polymorphisms of the genes genotyped
IFN-γ +874 A/T
IL-10 -1082 A/G
IL-10 -592 A/C
The study was approved by the Clinical Research Ethics Committee of the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster and included 476 Chinese patients with SARS (201 male, mean age = 39.8 ± 15.2) and 449 ethnically matched healthy controls from Red Cross (273 male, mean age = 29.1 ± 10.4). At least 95% of the patients were documented with SARS-CoV antibody seroconversion and/or detectable SARS-CoV RNA in respiratory secretions by RT-PCR.
IFN-γ +874A/T, IL-10 -1082G/A and -592A/C were genotyped by TaqMan system (Applied Biosystems, Foster City, CA, USA) as described previously . TNF-α -308 G/A was also genotyped by TaqMan system with same condition. The sequences of the primers were 5'-CCT GGT CCC CAA AAG AAA TG-3' and 5'-TCT TCT GGG CCA CTG ACT GA-3' and the probes were 6-FAM-TTG AGG GGC ATG GGG ACG G-TAMRA and VIC-TTG AGG GGC ATG AGG ACG GG-TAMRA.
The frequencies of genotypes and alleles of the 4 single nucleotide polymorphisms (SNPs) were compared between the SARS patients and healthy controls by 3 × 2 and 2 × 2 chi square test respectively. In case of significance, logistic regression was used for calculating OR with 95% CI and corresponding P-values between groups by controlling age and sex as covariables. The genotypes of all SNPs were tested for Hardy-Weinberg equilibrium (HWE) by chi square test.
Allele frequencies and genotype frequencies in SARS patients and controls*
SARS (n = 476)
Control (n = 449)
OR (95% CI)
5.19 (2.78 – 9.68)
2.57 (1.35 – 4.88)
2.23 (1.75 – 2.83)
IFN-γ +874A allele has been previously reported to be associated with infectious diseases such as tuberculosis, hepatitis B virus infection, and parvovirus infection [20–22], revealing its potential role of function in host defense against microbial infections. The mechanism by which the IFN-γ +874A/T allele influences the susceptibility to SARS may depend on its role in the regulation of IFN-γ production. The T allele of IFN-γ +874A/T provides a binding site for the transcription factor nuclear factor-κB (NF-κB), which is able to regulate IFN-γ expression . It is possible that low IFN-γ production may impair their anti-viral response against SARS-CoV, rendering these individuals more susceptible to this virus infection. Our observation that IFN-γ +874A allele was significantly associated with SARS-CoV infection suggests a genetic risk factor for SARS. The role of IFN-γ in antiviral response against SARS-CoV has also been supported by recent studies showing that IFN-γ can inhibit the replication of SARS-CoV in combination with IFN-β in vitro [24, 25].
IL-10 and TNF-α SNPs were also included in this study. They were chosen due to their potential regulation on protein expression level [26–28]. However, our present data did not show any significant association of these SNPs with SARS (Table 2). Nevertheless, we cannot exclude the role of IL-10 and TNF-α as the susceptibility genes for SARS, because other SNPs in these 2 genes may also be involved in gene expression regulation. Further association studies on other SNPs, which could alter the gene expression level are required to ascertain the relationship of IL-10 and TNF-α in SARS.
Genotype frequencies among survival and death SARS cases
Death (n = 57)
Survival (n = 415)
We demonstrated that IFN-γ +874A allele was significantly associated with SARS susceptibility in a dose dependent manner. Due to its role in regulating IFN-γ expression , this allele may be involved in the pathogenesis of SARS by altering the IFN-γ production.
This work is supported by the Outstanding Researcher Awards (YLL & JSMP), Postgraduate Studentships (WPC, GHWT, MWN) from the University of Hong Kong, the Research Fund for the Control of Infectious Diseases (03040302) from the Health, Welfare and Food Bureau of theHong Kong SAR Government and Edward Sai Kim Hotung Paediatric Education and Research Fund.
- Peiris JS, Lai ST, Poon LL, Guan Y, Yam LY, Lim W, Nicholls J, Yee WK, Yan WW, Cheung MT, Cheng VC, Chan KH, Tsang DN, Yung RW, Ng TK, Yuen KY, SARS study group: Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet. 2003, 361: 1319-25. 10.1016/S0140-6736(03)13077-2.View ArticlePubMedGoogle Scholar
- Peiris JS, Guan Y, Yuen KY: Severe acute respiratory syndrome. Nat Med. 2004, 10: S88-97. 10.1038/nm1143.View ArticlePubMedGoogle Scholar
- Lau YL, Peiris JM: Pathogenesis of severe acute respiratory syndrome. Curr Opin Immunol. 2005, 17: 404-10. 10.1016/j.coi.2005.05.009.View ArticlePubMedGoogle Scholar
- Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, Dwosh HA, Walmsley SL, Mazzulli T, Avendano M, Derkach P, Ephtimios IE, Kitai I, Mederski BD, Shadowitz SB, Gold WL, Hawryluck LA, Rea E, Chenkin JS, Cescon DW, Poutanen SM, Detsky AS: Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003, 289: 2801-9. 10.1001/jama.289.21.JOC30885.View ArticlePubMedGoogle Scholar
- Chan JW, Ng CK, Chan YH, Mok TY, Lee S, Chu SY, Law WL, Lee MP, Li PC: Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS). Thorax. 2003, 58: 686-9. 10.1136/thorax.58.8.686.View ArticlePubMedPubMed CentralGoogle Scholar
- Leung GM, Hedley AJ, Ho LM, Chau P, Wong IO, Thach TQ, Ghani AC, Donnelly CA, Fraser C, Riley S, Ferguson NM, Anderson RM, Tsang T, Leung PY, Wong V, Chan JC, Tsui E, Lo SV, Lam TH: The epidemiology of severe acute respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients. Ann Intern Med. 2004, 141: 662-73. Summary for patients in: Ann Intern Med 2004;141: I63.View ArticlePubMedGoogle Scholar
- Ip WK, Chan KH, Law HK, Tso GH, Kong EK, Wong WH, To YF, Yung RW, Chow EY, Au KL, Chan EY, Lim W, Jensenius JC, Turner MW, Peiris JS, Lau YL: Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005, 191: 1697-704. 10.1086/429631.View ArticlePubMedGoogle Scholar
- Zhang H, Zhou G, Zhi L, Yang H, Zhai Y, Dong X, Zhang X, Gao X, Zhu Y, He F: Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005, 192: 1355-61. 10.1086/491479.View ArticlePubMedGoogle Scholar
- Chan VS, Chan KY, Chen Y, Poon LL, Cheung AN, Zheng B, Chan KH, Mak W, Ngan HY, Xu X, Screaton G, Tam PK, Austyn JM, Chan LC, Yip SP, Peiris M, Khoo US, Lin CL: Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection. Nat Genet. 2006, 38: 38-46.View ArticlePubMedGoogle Scholar
- Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP: Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol. 1999, 17: 189-220. 10.1146/annurev.immunol.17.1.189.View ArticlePubMedGoogle Scholar
- Makhatadze NJ: Tumor necrosis factor locus: genetic organisation and biological implications. Hum Immunol. 1998, 59: 571-9. 10.1016/S0198-8859(98)00056-1.View ArticlePubMedGoogle Scholar
- Mulligan MS, Varani J, Dame MK, Lane CL, Smith CW, Anderson DC, Ward PA: Role of endothelial-leukocyte adhesion molecule 1 (ELAM-1) in neutrophil-mediated lung injury in rats. J Clin Invest. 1991, 88: 1396-406.View ArticlePubMedPubMed CentralGoogle Scholar
- Mulligan MS, Vaporciyan AA, Miyasaka M, Tamatani T, Ward PA: Tumor necrosis factor alpha regulates in vivo intrapulmonary expression of ICAM-1. Am J Pathol. 1993, 142: 1739-49.PubMedPubMed CentralGoogle Scholar
- 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: 2081-95. 10.1084/jem.170.6.2081.View ArticlePubMedGoogle Scholar
- 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. 10.1146/annurev.immunol.19.1.683.View ArticlePubMedGoogle Scholar
- Inoue G: Effect of interleukin-10 (IL-10) on experimental LPS-induced acute lung injury. J Infect Chemother. 2000, 6: 51-60. 10.1007/s101560050050.View ArticlePubMedGoogle Scholar
- Panuska JR, Merolla R, Rebert NA, Hoffmann SP, Tsivitse P, Cirino NM, Silverman RH, Rankin JA: Respiratory syncytial virus induces interleukin-10 by human alveolar macrophages. Suppression of early cytokine production and implications for incomplete immunity. J Clin Invest. 1995, 95: 2445-53.View ArticleGoogle Scholar
- Standiford TJ, Strieter RM, Lukacs Nw, Kunkel SL: Neutralization of IL-10 increases lethality in endotoxemia. Cooperative effects of macrophage inflammatory protein-2 and tumor necrosis factor. J Immunol. 1995, 155: 2222-9.PubMedGoogle Scholar
- Kalechman Y, Gafter U, Gal R, Rushkin G, Yan D, Albeck M, Sredni B: Anti-IL-10 therapeutic strategy using the immunomodulator AS101 in protecting mice from sepsis-induced death: dependence on timing of immunomodulating intervention. J Immunol. 2002, 169: 384-92.View ArticlePubMedGoogle Scholar
- Tso HW, Ip WK, Chong WP, Tam CM, Chiang AKS, Lau YL: Association of interferon gamma and interleukin 10 genes with tuberculosis in Hong Kong Chinese. Genes Immun. 2005, 6: 358-63. 10.1038/sj.gene.6364189.View ArticlePubMedGoogle Scholar
- Ben-Ari Z, Mor E, Papo O, Kfir B, Sulkes J, Tambur AR, Tur-Kaspa R, Klein T: Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am J Gastroenterol. 2003, 98 (1): 144-50. 10.1111/j.1572-0241.2003.07169.x.View ArticlePubMedGoogle Scholar
- Kerr JR, McCoy M, Burke B, Mattey DL, Pravica V, Hutchinson IV: Cytokine gene polymorphisms associated with symptomatic parvovirus B19 infection. J Clin Pathol. 2003, 56: 725-7. 10.1136/jcp.56.10.725.View ArticlePubMedPubMed CentralGoogle Scholar
- Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV: 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. 2000, 61: 863-6. 10.1016/S0198-8859(00)00167-1.View ArticlePubMedGoogle Scholar
- Scagnolari C, Vicenzi E, Bellomi F, Stillitano MG, Pinna D, Poli G, Clementi M, Dianzani F, Antonelli G: Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons. Antivir Ther. 2004, 9: 1003-11.PubMedGoogle Scholar
- Sainz B, Mossel EC, Peters CJ, Garry RF: Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Virology. 2004, 329: 11-7. 10.1016/j.virol.2004.08.011.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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: 1101-8. 10.1002/1529-0131(199906)42:6<1101::AID-ANR6>3.0.CO;2-Y.View ArticlePubMedGoogle Scholar
- Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW: Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A. 1997, 94: 3195-9. 10.1073/pnas.94.7.3195.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/6/82/prepub
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