Genes encoding IRF1 and IRF8 protein have been proposed as candidate tuberculosis susceptibility genes. In order to elucidate whether the IRF1 and IRF8 variants were associated with tuberculosis susceptibility, we conducted a case-control study consisting of 495 controls and 452 ethnically matched cases with tuberculosis in a Chinese population. Seven haplotype tagging single-nucleotide polymorphisms (tagSNPs) (rs2057656; rs2706381; rs2070724; rs2070721; rs2549008; rs2549007; rs2706386) from HapMap database were analyzed, which provided an almost complete coverage of the genetic variations in the IRF1 gene. Fifteen tagSNPs (rs12924316; rs182511; rs305080; rs2292980; rs925994; rs424971; rs16939967; rs11117415; rs4843860; rs9926411; rs8064189; rs12929551; rs10514611; rs1044873; rs6638) were observed in the IRF8 gene. All these tagSNPs were genotyped by SNPstream genotyping and SNaPshot typing. None of the seven tagSNPs was individually associated with tuberculosis in the IRF1 gene. In the IRF8 gene, interestingly, we found that three tagSNPs (rs925994 and rs11117415 located in the intron region; rs10514611 located in the 3′UTR) were associated with risk of tuberculosis after Bonferroni correction. Per allele OR was 1.75 (95% CI 1.35~2.27, P = 0.002), 4.75 (95% CI 2.16~10.43, P = 0.002) and 3.39 (95% CI 1.60~7.20, P = 0.015) respectively. Luciferase reporter gene assay showed that the construct that contained the non-risk allele C of rs10514611 showed significantly higher luciferase activity than did the risk T allele (P<0.01), which implied rs10514611 was a potential functional SNP site. Our results indicated that the IRF8 gene might participate in genetic susceptibility to tuberculosis in a Chinese population.
van der Eijk EA, van de Vosse E, Vandenbroucke JP, van Dissel JT (2007) Heredity versus environment in tuberculosis in twins: the 1950s United Kingdom Prophit Survey Simonds and Comstock revisited. Am J Respir Cirt Care Med 176: 1281–1288.
Stead WW, Senner JW, Reddick WT, Lofgren JP (1990) Racial differences in susceptibility to infection by Mycobacterium tuberculosis. N Eng J Med 322: 422–427.
Surcel HM, Troye-Blomberg M, Paulie S, Andersson G, Moreno C, et al. (1994) Th1/Th2 profiles in tuberculosis, based on the proliferation and cytokine response of blood lymphocytes to mycobacterial antigens. Immunology 81: 171–176.
Okamoto M, Hasegawa Y, Hara T, Hashimoto N, Imaizumi K, et al. (2005) T-helper type 1/T-helper type 2 balance in malignant pleural effusions compared to tuberculous pleural effusions. Chest 128: 4030–4035.
Bovolenta C, Driggers PH, Marks MS, Medin JA, Politis AD, et al. (1994) Molecular interactions between interferon consensus sequence binding protein and members of the interferon regulatory factor family. Pro Natl Acad Sci U S A 91: 5046–5050.
Taki S, Sato T, Ogasawara K, Fukuda T, Sato M, et al. (1997) Multistage regulation of Th1-type immune responses by the transcription factor IRF-1. Immunity 6: 673–679.
Harada H, Takahashi E, Itoh S, Harada K, Hori TA, et al. (1994) Structure and regulation of the human interferon regulatory factor (IRF-1) and IRF-2 gene: implication for a gene network in the interferon system. Mol Cell Biol 14: 1500–1509.
Marquis JF, LaCourse R, Ryan L, North RJ, Gros P (2009) Disseminated and rapidly fatal tuberculosis in mice bearing a defective allele at IFN regulatory factor 8. J Immunol 182: 3008–3015.
Ogasawara K, Hida S, Azimi N, Tagaya Y, Sato T, et al. (1998) Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature 391: 700–703.
Schedel M, Pinto LA, Schaub B, Rosenstiel P, Cherkasov D, et al. (2008) IRF-1 gene variations influence IgE regulation and atopy. Am J Respir Cirt Care Med 177: 613–621.
Lee YJ, Kang SW, Song JK, Baek HJ, Choi HJ, et al. (2007) Associations between interferon regulatory factor-1 polymorphisms and Behcet’s disease. Hum Immunol 68: 770–778.
Mangano VD, Luoni G, Rockett KA, Sirima BS, Konate A, et al. (2008) Interferon regulatory factor -1 polymorphisms are associated with the control of Plasmodium falciparum infection. Genes Immun 9: 122–129.
Vollstedt S, Yuliwulandari R, Okamoto K, Lien LT, Keicho N, et al. (2009) No evidence for association between the interferon regulatory factor 1 (IRF-1) gene and clinical tuberculosis. Tuberculosis(Edinb) 89: 71–76.
Zhang K, Deng M, Chen T, Waterman MS, Sun F (2002) A dynamic programming algorithm for haplotype block partitioning. Proc Natl Acad Sci U S A 99: 7335–7339.
Zhang K, Qin ZS, Liu JS, Chen T, Waterman MS, et al. (2004) Haplotype block partitioning and tag SNP selection using genotype data and their applications to association studies. Genome Res 14: 908–916.
Xu Z, Kaplan NL, Taylor JA (2007) TagSNP selection for candidate gene association studies using HapMap and gene resequencing data. Eur J Hum Genet 15: 1063–1070.
Qiao YM, Prabhakar S, Canova A, Hoshino Y, Weiden M, et al. (2004) Posttranscriptional inhibition of gene expression by Mycobacterium tuberculosis offsets transcriptional synergism with IFN-γ and posttranscriptional up-regulation by IFN-γ. J Immunol 172: 2935–2943.
Zhao J, Kong HJ, Huang B, Yang M, Zhu C, et al. (2006) IRF-8/interferon (IFN) consensus sequence-binding protein is involved in Toll-like receptor (TLR) signaling and contributes to the cross-talk between TLR and IFN-gamma signaling pathways. J Biol Chem 281: 10073–10080.
Qi CF, Li Z, Raffeld M, Wang H, Kovalchuk AL, et al. (2009) Differential expression of IRF8 in subsets of macrophages and dendritic cells and effects of IRF8 deficiency on splenic B cell and macrophage compartments. Immunol Res 45: 62–74.
Alter-Koltunoff M, Goren S, Nousbeck J, Feng CG, Sher A, et al. (2008) Innate immunity to intraphagomal pathogens is mediated by interferon regulatory factor 8 (IRF-8) that stimulates the expression of macrophage-specific Nramp1 through anatonizing repression by c-Myc. J Biol Chem 283: 2724–2733.
Turcotte K, Gauthier S, Tuite A, Mullick A, Malo D, et al. (2005) A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia-like syndrome in BXH-2 mice. J Exp Med 201: 681–690.
