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Polymorphism within the Interferon-/Receptor Complex Is Associated with Pulmonary Tuberculosis

Graham S. Cooke, Sarah J. Campbell, Jackson Sillah, Per Gustafson, Boubacar Bah, Georgio Sirugo, Steve Bennett, Keith P. W. J. McAdam, Oumou Sow, Christian Lienhardt and Adrian V. S. Hill

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; London School of Hygiene and Tropical Medicine, London, United Kingdom; Medical Research Council Laboratories, Fajara, The Gambia; CHU Ignace Deen, Conakry, Republique de Guinee; Danish Epidemiology Science Centre, Bissau, Guinea-Bissau; and Institut de Recherche pour le Developpement (IRD), Dakar, Senegal

Correspondence and requests for reprints should be addressed to Dr. Graham S. Cooke, M.R.C.P., Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Churchill Hospital, Headington, Oxford OX3 7BN, UK. E-mail: graham.cooke{at}st-marys.nhs.uk

	ABSTRACT

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Rationale: Interferon- (IFN-) is of central interest in the study of tuberculosis. A number of single-gene mutations have been identified in the IFN- signaling pathway that predispose to severe mycobacterial disease, but the relevance of polymorphism within these genes to the common phenotype of tuberculosis remains unclear.

Methods: A total of 1,301 individuals were included in a large, detailed study of West African populations with pulmonary tuberculosis. We investigated disease association with the genes encoding IFN- and its receptor subunits (IFNG, IFNGR1, and IFNGR2).

Results: Within the IFNG gene, two promoter variants showed evidence of novel disease association: –1616GG (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.11–2.00; p = 0.008) and +3234TT (OR, 1.40; 95% CI, 1.09–1.80; p = 0.009). The +874AA genotype was not significantly more frequent among cases over control subjects (OR, 1.16; 95%CI, 0.89–1.51; p = 0.25). In addition, novel disease association was also found with the –56CC genotype of the IFNGR1 promoter (OR, 0.75; 95% CI, 0.57–0.99; p = 0.041). No disease association was seen with the IFNGR2 locus.

Conclusions: These results provide evidence of a significant role for genetic variation at the IFNG locus and provide detailed understanding of the genetic mechanisms underlying this association. The disease association with IFNGR1 is novel, and together these findings support the hypothesis that genetically determined variation in both IFN- production and responsiveness influences the risk of developing tuberculosis.

Key Words: interferon- • polymorphism • receptor • tuberculosis

The interferon- (IFN-) signaling pathway is of central interest in the study of tuberculosis, a disease that still kills nearly two million people a year (1). The potential importance of the pathway is highlighted by the discovery of several families with Mendelian susceptibility to mycobacterial disease (MSMD; Mendelian Inheritance in Man [MIM] 209950) who have mutations in one of two subunits of the IFNG receptor (IFNGR1 and IFNGR2) (2). Although there are no families identified with mutation in IFNG itself, recent data suggest a more common polymorphism at position +874 is associated with the risk of tuberculosis in different populations (3–5).

IFN- is an acid-labile protein produced by CD4⁺ T cells (and other cell types, including natural killer cells, CD8⁺ T cells, and macrophages). It acts as a regulator of gene expression through activation of a receptor complex comprising two subunits, each encoded by a different gene (IFNGR1 on chromosome 6q23-4 and IFNGR2 on chromosome 21q22.1–22.2). Homodimers of IFN- interact with both receptor proteins (6), leading to receptor dimerization (7), and each of the three molecules plays a nonredundant role in ligand-activated receptor signaling.

In the most comprehensive investigation of the pathway to date, we have performed a large and detailed study of polymorphism within the following three genes: IFNG, IFNGR1, and IFNGR2. All are strong candidate genes for the complex phenotype of tuberculosis. Any association within these genes would provide insight into the clinically important immune mechanisms influencing this persistent disease and provide an opportunity to assess the extent to which rare single-gene disorders can inform our understanding of complex infectious diseases.

	METHODS

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Populations Studied
This study was performed as part of a large case-control study of adult pulmonary tuberculosis in three West African countries described in detail previously (10, 11), and not including subjects studied previously by Bellamy and colleagues (12–14) or Awomoyi and colleagues (8, 15). The study uses population collections from the Gambia, Guinea Bissau, and the Republic of Conakry. All cases were confirmed by either two consecutive smear-positive samples or a positive Mycobacterium tuberculosis (MTB) culture. Both HIV-positive and HIV-negative cases were included, the prevalence of each differing among countries (10). This study included a total of 682 cases and 619 control subjects, providing at least 80% power to detect an odds ratio (OR) of 2 for a genotype of frequency between 4 and 50%. DNA was available from the parents of 210 affected Gambians to allow a family-based test of association and estimation of haplotype frequencies. Informed consent was obtained from patients or their parents or guardians. Ethical approval was provided by the joint Gambian Government/Medical Research Council Ethical Committee, the Ministry of Public Health (MINSAP, Guinea-Bissau), and the National Ethics Committee, Ministry of Health, Conakry, Republique de Guinee. Human experimentation guidelines of these ministries were followed.

Genotyping
DNA was extracted using the Nucleon BACC2 DNA extraction kit (Nucleon Bioscience, Manchester, UK). DNA concentrations were determined using the PicoGreen kit (Molecular Probes, Paisley, UK). Initial typing of the +874A/T polymorphism was performed with an amplification refractory mutation system (ARMS) reaction similar to that first described by Pravica and colleagues (16). Reaction mix included 5 µl DNA at 10 ng/µl, 5 µl H₂O, 1.5 µl 10x polymerase chain reaction buffer, 1.5 µl Mg²⁺, 0.3 µl of 8-mM deoxynucleotide triphosphates (dNTPs), 0.3 µl of 10-µM allele-specific and common primers, and 0.3 µl of 2-µM control primers (human growth hormone [HGH]), 0.08 µl Taq Gold. Reaction conditions were 95°C for 1 min followed by 10 cycles of 95°C for 15 s, 62°C for 50 s, and 72°C for 40 s, then 20 cycles of 95°C for 20 s, 56°C for 50 s, and 72°C for 50 s. This genotyping was subsequently confirmed using the Sequenom genotyping system, which uses mass spectrometry (MALDI-TOF) to discriminate products by their absolute mass. All other polymorphisms were typed using the Sequenom system.

Single-Nucleotide Polymorphism Selection
The available literature and publicly accessible databases were used to identify single-nucleotide polymorphisms (SNPs). In the case of IFNG, all SNPs previously associated with infectious disease were studied. No known amino acid–changing polymorphisms have yet been identified in this gene, and thus SNPs at the following positions were selected to cover the four exons: –1616; –308, referred to elsewhere sometimes as –179 (17, 18); +874 (3–5); +1987 (19); +3234; +3686; and +5173. Within IFNGR1, two noncoding SNPs were studied at positions –56 (20) and +95 (21) alongside two exonic variants, H318P (20) and L467P (22). Within IFNGR2, two nonsynonymous polymorphisms from exon 2 (T58R and R64Q [23]), were studied alongside one variant from intron 1 (GenBank NT_011512).

Statistical Methods
Analysis of case-control data was performed with SPSS version 11 (SPSS, Inc., Chicago, IL). Overall genotype frequencies were studied with a 3 x 2 ² test. Binary logistic regression was used to assess the effect of genotype on disease outcome, adjusted for age, sex, ethnicity, and HIV status. Disease association within the families was studied using the transmission disequilibrium test (TDT) (24), using the TRANSMIT program (25). GENEHUNTER (26) was used to generate haplotypes prior to analysis within GOLD (Graphical Overview of Linkage Disequilibrium) (27) to estimate linkage disequilibrium (LD) coefficients.

	RESULTS

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Allele Frequencies
For each SNP selected above, initial genotyping was performed on 94 cases and 94 control subjects to establish allele frequencies. One SNP was excluded from further study because it appeared to be in complete LD with another polymorphism (IFNGR1 +95). The allele frequencies for each polymorphism in Gambian control subjects are shown in Table 1.

LD mapping suggests strong LD exists between several of these loci, and a strong block of LD exists within the gene itself (data not shown). The +874 polymorphism is in significant LD with two other polymorphisms that do show evidence of disease association, namely those at –1616 (D' 0.79, p < 0.001) and +3234 (D' 0.66, p < 0.001). Overall genotype distributions for the associated SNPs are shown in Table 2. The –1616 promoter polymorphism is associated with disease, in particular the –1616GG genotype (OR, 1.49; 95% CI, 1.11–2.00; p = 0.008), and a similar trend in genotype distribution is seen across the three countries studied (–1616GG: Gambia: 31.3% cases, 24.5% control subjects; Guinea Bissau: 22.2% cases, 20.8% control subjects; and Conakry: 33.0% cases and 24.8% control subjects). The +3234 polymorphism also showed evidence of disease association (+3234TT: OR, 1.40; 95% CI, 1.09–1.80; p = 0.009) and a similar trend in genotype distribution across three countries (+3234TT: Gambia: 57.3% cases, 53.1% control subjects; Guinea Bissau: 55% cases, 48.3% control subjects; and Conakry: 52.4% cases and 43.6% control subjects). Distribution of genotypes between case and control subjects was similar in the HIV-negative and the small number of HIV-positive individuals (data not shown).

	DISCUSSION

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IFN-–mediated immune activation appears to have an important role in immunity to intracellular pathogens, both in mice and humans, but its role in human tuberculosis still remains unclear (28). Early studies (29, 30) demonstrated that mice with disruption of the ifng gene are more susceptible to infection by MTB than wild-type strains. Macrophages from these mice have impaired activation and treating the mice with recombinant IFN- slows (though does not stop) their rapidly progressive disease (30). Knockout (ifng^–/–) mice given bacillus Calmette-Guérin (BCG) engineered to produce IFN- control infection better than those given BCG alone (31), and IFN- production within the lung appears to be an important component of this response (Reuter and colleagues, unpublished data, and Reference 32).

Despite the accumulating data for a role in mice, it has been harder to establish the importance of IFN- in human tuberculosis. Studies of IFN-–mediated immune responses in clinical cohorts present a complex picture. Although resting macrophages are unable to kill intracellular pathogens such as MTB, activated macrophages can. IFN- is critical to this activation and there are reports that measurable levels of IFN- are lower in individuals with active tuberculosis (33, 34) than control subjects, suggesting a protective role for the cytokines. However, high interferon levels are found in many affected individuals as well as healthy purified protein derivative (PPD+) control subjects, and this has led some to conclude that IFN- is an unreliable correlate of protection (28). The observation that IFN- levels are high at sites of infection hints at the fact that responsiveness to IFN-, rather than its production, might be the more important determinant of disease (35). Consistent with this hypothesis is the observation that MTB can influence changes in genes "downstream" of the receptor complex (36) and thus variability "upstream" of the receptor complex might be less important in determining disease outcome.

It has been more formally suggested that IFN- activity is a continuous, genetically controlled trait with genetic variability in both the production of, and responsiveness to, IFN- (37), although until recently there was little evidence to support a role for variability in IFN- production.

The data above demonstrate that both the –1616GG and the +3234TT genotypes of IFNG are associated with pulmonary tuberculosis in West African populations. The size of the effect in each case is small (adjusted OR, 1.49 and 1.30, respectively), but, in contrast to many effects seen in complex genetics, the same trend is seen consistently in the three populations studied, suggesting it is unlikely to be due to chance. This provides the first evidence that genetically determined control of IFNG expression is associated with disease in these West African populations and supports the hypothesis that production of IFN- is a genetically controlled trait that influences disease outcome. This knowledge should inform strategies targeting the IFN- pathway in vaccine development (both directly and indirectly) and could lead to a re-evaluation of IFN- as a therapeutic adjuvant in disease (38).

The significance of these findings stands alone without a detailed understanding of the mechanisms underlying them. However, the +3234 polymorphism is adjacent to an octamer binding transcription factor 1 (OCT-1) binding site and alters a TAAA transcription motif that might be clinically relevant. More likely, the –1616A promoter allele is part of a GATA motif that is lost in the presence of the –1616G allele (GGTA), and this could have been functionally significant. GATA transcription factors are known to play a role in T-cell activity, and appear to play a role in Th1/Th2 differentiation.

The lack of disease association with the +874 polymorphism does not preclude this as a disease-causing allele. It is still possible that the association seen with both the –1616 and +3234 polymorphisms is a result of highly significant LD with the +874AT polymorphism. The ORs observed are small and even a study as large as this might not have sufficient power in these populations to detect an effect due to the +874 variant. This is not unusual; environmental factors such as malnutrition are likely to dilute any genotypic effect seen in these populations and it is well recognized that replication datasets often need to be considerably larger than those originally reporting an association. It will be important for those groups that have reported association with the +874 polymorphism to examine the other SNPs mentioned here. The size of the observed effect does have important implications for replication studies. For a study to have 80% power to detect an effect of this magnitude, even with a common genotype, it is likely to require a sample size of approximately 1,000 cases and control subjects. From our understanding of the role of IFNGR1 in severe mycobacterial infection and the evidence of a role for IFNG itself, IFNGR1 is a strong candidate gene for tuberculosis. However, before now, there was no evidence implicating the IFNGR1 polymorphism in susceptibility to the complex phenotype of tuberculosis. The only published work addressing this question is a small Croatian case-control study, which found marginal disease association with a microsatellite in the noncoding region of the gene (39), a finding that was not replicated in another Gambian study (9).

There are convincing reports of infectious phenotypes that show linkage to the IFNGR1 locus, including severe hepatic fibrosis in Schistosoma mansoni infection (40) and a study of IgG immune responses to Helicobacter pylori infection, where it was suggested that the –56C/T promoter polymorphism might play an important role (20). Weaker evidence of linkage also exists between the IFNGR1 locus and post Kala-azar dermal leishmaniasis (PKDL) (41).

Until recently, evidence for allelic association with disease within this locus has been lacking. However, in a subgroup analysis of the most common ethnic group in the Gambia, Koch and colleagues observed that heterozygosity for the –56C/T polymorphism was associated with protection against severe malaria (21). A recent smaller Gabonese study failed to replicate this finding but did present data suggesting this polymorphism alters gene expression (42), with the –56C allele producing a lower response in a luciferase assay to phytohemagglutination (PHA) stimulation.

There is evidence from an in vitro model of cell expression that constructs bearing the –56C allele produce less transcriptional activity in a standard assay system (42). If these findings can be translated into the clinical setting, we might expect individuals with the –56CC genotype to express less IFNGR1 receptor on the cell surface. It is perhaps surprising that this genotype is associated with protection from pulmonary tuberculosis in West African populations. A reduced immune response mediated by IFNGR1 could protect against pulmonary immunopathology, but given everything else that is known about IFN-, this explanation seems unlikely. More plausibly is that either another variant exists in LD that might explain the disease association or that the functional role of this polymorphism has not yet been fully characterized. The in vitro functional data are also not conclusive. Although the –56C allele is associated with reduced expression in a pGL3/basic vector system on stimulation with PHA, the oligonucleotide bearing the –56C allele binds more nuclear extract from B cells. The authors suggest that this might be due to inhibitory binding of AP-4 (42), particularly because the two sites are close together, but equally, the expression vector results might not be an accurate reflection of in vivo behavior.

These data are the first to find evidence of disease association between IFNGR1 and tuberculosis. The data suggest that variation in the IFNGR1 receptor promoter does play a role, albeit a small one, in the pathogenesis of tuberculosis, and previous studies may well have lacked the power needed to see these effects. These findings are consistent with the hypothesis that both production of, and responsiveness to, IFN- have genetic determinants. It is likely that the relative importance of each of these factors will differ among populations, dependent on the nature and frequency of variants present, but in these populations, variation within IFNG was more strongly associated with disease.

Although a small effect, the identification of an association with IFNGR1 is an important finding. It suggests that polymorphism within this gene, previously associated with monogenic susceptibility to mycobacterial disease (MSMD, MIM 209950), influences the more common, complex phenotype of tuberculosis. Although the mutation within the gene is highly penetrating, the more frequent polymorphism within the gene does not appear to exert a major effect in these populations. Nonetheless, this is important in our understanding of the IFNG pathway's role in mediating immunity to MTB and suggests one host mechanism whereby individuals' responsiveness to IFN- will influence the likelihood of developing tuberculosis.

There are only a few reports of association between the IFNGR2 polymorphism and disease. A study of IgE levels in atopic British whites has found an association with the R64Q variant (23). The same polymorphism is associated with an increased risk of sytemic lupus erythematosus (SLE) in a Japanese population, but only in the presence of a heterozygous Met/Val genotype at codon 14, a variant not found in West Africa (43). No evidence is found here for an association between IFNGR2 variants and tuberculosis. This is perhaps surprising because studies of families with nonfunctional IFNGR2 proteins tell us that the molecule plays a nonredundant role in immunity to nontuberculous mycobacteria. There are several potential explanations. It is possible that the sample size is too small, but there is still considerable power in this study to detect even a modest allele or genotypic effect. It might well be that none of the variants studied has a biological function. The critical ligand binding sites on the extracellular region of IFNGR2 have not yet been identified and the two coding variants might not influence the biological function of the receptor complex. In the absence of specific in vitro data addressing this question, it is impossible to know, but the fact that two of the variants studied change the protein structure, and have been associated with other disease, suggests they might have a functional role in other diseases. Interestingly, although evidence is emerging of cases of tuberculosis in individuals with IFNG and IFNGR1 mutation, none has yet been observed with IFNGR2. These IFNGR2 mutations are rarer, but this raises the possibility that IFNGR2 signaling might be redundant in immunity to MTB but not nontuberculous mycobacteria (NTM), although the data here alone cannot substantiate such a claim.

In summary, the IFNG genotype (+874AA) previously associated with disease was seen in excess in cases compared with control subjects, but not significantly so. Two other variants in strong LD with the +874 variant did show evidence of disease association, confirming a significant role of genetic variation at the IFNG locus and providing a more detailed understanding of the genetic mechanisms underlying the disease association.

The absence of association with IFNGR2 is interesting, but firm conclusions cannot be drawn without further work. The disease association with IFNGR1 is novel, and together these findings support the hypothesis that genetically determined variation in both IFN- production and responsiveness influence disease. Furthermore, these findings illustrate some of the limitations of the important models of MSMD (MIM 209950) in improving our understanding of the complex phenotype of tuberculosis.

	Acknowledgments

 
The authors thank all those who participated in this study. They also thank Oliver Koch for his helpful discussions regarding the study of IFNGR1 and Lisa Bornman for preparation of DNA samples.

	FOOTNOTES

 
Supported by the Wellcome Trust (fellowships to G.S.C., S.J.C., A.V.S.H.). Samples were collected as part of a European Commission funded project (contract no. IC18CT980375), coordinated by C.L. Sample collection in the Gambia was supported in part by the Medical Research Council (G0000690 to G.S.).

Professor Steve Bennett died in March 2003.

Originally Published in Press as DOI: 10.1164/rccm.200601-088OC on May 11, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form January 22, 2006; accepted in final form May 10, 2006

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