Browsing by Author "Thye, T."
Now showing 1 - 14 of 14
Results Per Page
Sort Options
Item ALOX5 variants associated with susceptibility to human pulmonary tuberculosis(Oxford University Press, 2008-04) Herb, F.; Thye, T.; Niemann, S.; Browne, E.N.L.; Chinbuah, M.A.; Gyapong, J.; Osei, I.; Owusu-Dabo, E.; Werz, O.; Rüsch-Gerdes, S.; Horstmann, R.D.; Meyer, C.G.The 5-lipoxygenase (ALOX5)-derived lipid mediators leukotrienes and lipoxins have regulatory functions in inflammation by modulating activities of immune cells and cytokine production. Recently, it was shown in ALOX5 -/- mice that host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase (5-LO). ALOX5 polymorphisms were genotyped in 1916 sputum-positive patients with pulmonary tuberculosis (TB) from Ghana and in 2269 exposed, apparently healthy controls. Polymorphisms of a variable number of tandem repeats (VNTR) of the ALOX5 promoter and of the exonic non-synonymous variant g.760G>A were analysed by fragment length determination and fluorescence resonance energy transfer, respectively, and DNA sequencing. Mycobacterial lineages of >1400 isolates were differentiated biochemically and genetically. Carriers of one variant (n repeats # 5) and one wild-type VNTR allele (n = 5) or of the exonic allele g.760A had a higher risk of TB [P corrected = 0.026, odds ratio (OR) 1.19 (95% CI 1.04-1.37) and P corrected = 0.026, OR 1.21 (95% CI 1.04-1.41), respectively]. The association of the exonic variant was stronger in infections caused by the mycobacterial lineage M. africanum West-African 2 [P corrected = 0.024, OR 1.70; (95% CI 1.2-2.6)]. Determination of haplotypes revealed the strongest associaton with TB for the 'non-5/760A' haplotype compared with the 'non-5/760G' haplotype (P = 0.003, OR 1.50). Our observation of an association of ALOX5 variants with susceptibility to TB contributes evidence of the importance of 5-LO products to the regulation of immune responses to M. tuberculosis.Item Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains(2009-09) Intemann, C.D.; Thye, T.; Niemann, S.; Browne, E.N.L.; Chinbuah, M.A.; Enimil, A.; Gyapong, J.; Osei, I.; Owusu-Dabo, E.; Helm, S.; Rüsch-Gerdes, S.; Horstmann, R.D.; Meyer, C.G.The human immunity-related GTPase M (IRGM) has been shown to be critically involved in regulating autophagy as a means of disposing cytosolic cellular structures and of reducing the growth of intracellular pathogens in vitro. This includes Mycobacterium tuberculosis, which is in agreement with findings indicating that M. tuberculosis translocates from the phagolysosome into the cytosol of infected cells, where it becomes exposed to autophagy. To test whether IRGM plays a role in human infection, we studied IRGM gene variants in 2010 patients with pulmonary tuberculosis (TB) and 2346 unaffected controls. Mycobacterial clades were classified by spoligotyping, IS6110 fingerprinting and genotyping of the pks1/15 deletion. The IRGM genotype -261TT was negatively associated with TB caused by M. tuberculosis (OR 0.66, CI 0.52-0.84, P nominal 0.0009, P corrected 0.0045) and not with TB caused by M. africanum or M. bovis (OR 0.95, CI 0.70-1.30. P 0.8). Further stratification for mycobacterial clades revealed that the protective effect applied only to M. tuberculosis strains with a damaged pks1/15 gene which is characteristic for the Euro-American (EUAM) subgroup of M. tuberculosis (OR 0.63, CI 0.49-0.81, Pnominal 0.0004, Pcorrected 0.0019). Our results, including those of luciferase reporter gene assays with the IRGM variants -261C and -261T, suggest a role for IRGM and autophagy in protection of humans against natural infection with M. tuberculosis EUAM clades. Moreover, they support in vitro findings indicating that TB lineages capable of producing a distinct mycobacterial phenolic glycolipid that occurs exclusively in strains with an intact pks1/15 gene inhibit innate immune responses in which IRGM contributes to the control of autophagy. Finally, they raise the possibility that the increased frequency of the IRGM -261TT genotype may have contributed to the establishment of M. africanum as a pathogen in the West African population.Item Autophagy Gene Variant IRGM 2261T Contributes to Protection from Tuberculosis Caused by Mycobacterium tuberculosis but Not by M. africanum Strains(PLoS Pathogens, 2009) Intemann, C.D.; Thye, T.; Niemann, S.; Browne, E.N.L.; Chinbuah, M.A.; Enimil, A.; Gyapong, J.O.; Osei, I.; Owusu-Dabo, E.; Helm, S.; Rüsch-Gerdes, S.; Horstmann, R.D.; Meyer, C.G.The human immunity-related GTPase M (IRGM) has been shown to be critically involved in regulating autophagy as a means of disposing cytosolic cellular structures and of reducing the growth of intracellular pathogens in vitro. This includes Mycobacterium tuberculosis, which is in agreement with findings indicating that M. tuberculosis translocates from the phagolysosome into the cytosol of infected cells, where it becomes exposed to autophagy. To test whether IRGM plays a role in human infection, we studied IRGM gene variants in 2010 patients with pulmonary tuberculosis (TB) and 2346 unaffected controls. Mycobacterial clades were classified by spoligotyping, IS6110 fingerprinting and genotyping of the pks1/15 deletion. The IRGM genotype 2261TT was negatively associated with TB caused by M. tuberculosis (OR 0.66, CI 0.52– 0.84, Pnominal 0.0009, Pcorrected 0.0045) and not with TB caused by M. africanum or M. bovis (OR 0.95, CI 0.70–1.30. P 0.8). Further stratification for mycobacterial clades revealed that the protective effect applied only to M. tuberculosis strains with a damaged pks1/15 gene which is characteristic for the Euro-American (EUAM) subgroup of M. tuberculosis (OR 0.63, CI 0.49– 0.81, Pnominal 0.0004, Pcorrected 0.0019). Our results, including those of luciferase reporter gene assays with the IRGM variants 2261C and 2261T, suggest a role for IRGM and autophagy in protection of humans against natural infection with M. tuberculosis EUAM clades. Moreover, they support in vitro findings indicating that TB lineages capable of producing a distinct mycobacterial phenolic glycolipid that occurs exclusively in strains with an intact pks1/15 gene inhibit innate immune responses in which IRGM contributes to the control of autophagy. Finally, they raise the possibility that the increased frequency of the IRGM 2261TT genotype may have contributed to the establishment of M. africanum as a pathogen in the West African population.Item Common variants at 11p13 are associated with susceptibility to tuberculosis(Nature Genetics, 2012) Thye, T.; Owusu-Dabo, E.; Vannberg, F.O.; van Crevel, R.; Curtis, J.; Sahiratmadja, E.; Balabanova, Y.; Ehmen, C.; Muntau, B.; Ruge, G.; Sievertsen, J.; Gyapong, J.; Nikolayevskyy, V.; Hill, P.C.; Sirugo, G.; Drobniewski, F.; van de Vosse, E.; Newport, M.; Alisjahbana, B.; Nejentsev, S.; Ottenhoff, T.H.; Hill, A.V.; Horstmann, R.D.; Meyer, C.G.After imputation of data from the 1000 Genomes Project into a genome-wide dataset of Ghanaian individuals with tuberculosis and controls, we identified a resistance locus on chromosome 11p13 downstream of the WT1 gene (encoding Wilms tumor 1). The strongest signal was obtained at the rs2057178 SNP (P = 2.63 × 10−9). Replication in Gambian, Indonesian and Russian tuberculosis case-control study cohorts increased the significance level for the association with this SNP to P = 2.57 × 10−11.Item CTLA4 Autoimmunity-Associated Genotype Contributes to Severe Pulmonary Tuberculosis in an African Population(PLoS ONE, 2009) Thye, T.; Scarisbrick, G.; Browne, E.N.L.; Chinbuah, M.A.; Gyapong, J.O.; Osei, I.; Owusu-Dabo, E.; Niemann, S.; Rüsch-Gerdes, S.; Meyer, C.G.; Horstmann, R.D.The gene of Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA4), a negative regulator of T lymphocytes, contains a singlenucleotide polymorphism (SNP) at position +6230A-.G (ct60A-.G), which has been found associated with several autoimmune diseases and appears to reduce T-cell inhibitory activity. In Ghana, West Africa, we compared the frequencies of CTLA4 +6230 A/G and 6 haplotype-tagging SNPs in 2010 smear-positive, HIV-negative patients with pulmonary tuberculosis (TB) and 2346 controls matched for age, gender and ethnicity. We found no difference in allele frequencies between cases and controls. However, +6230A and a distinct CTLA4 haplotype and a diplotype comprising the +6230A allele were significantly less frequent among cases with large opacities in chest radiographs compared to those with small ones (Pcorrected [cor] = 0.002, Pcor = 0.00045, P = 0.0005, respectively). This finding suggests that an increased T-cell activity associated with the CTLA4 +6230G allele contributes to pathology rather than to protection in pulmonary TB.Item Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2.(2010-09) Thye, T.; Vannberg, F.O.; Wong, S.H.; Owusu-Dabo, E.; Osei, I.; Gyapong, J.; Sirugo, G.; Sisay-Joof, F.; Enimil, A.; Chinbuah, M.A.; Floyd, S.; Warndorff, D.K.; Sichali, L.; Malema, S.; Crampin, A.C.; Ngwira, B.; Teo, Y.Y.; Small, K.; Rockett, K.; Kwiatkowski, D.; Fine, P.E.; Hill, P.C.; Newport, M.; Lienhardt, C.; Adegbola, R.A.; Corrah, T.; Ziegler, A.; African TB Genetics Consortium; Wellcome Trust Case Control Consortium; Morris, A.P.; Meyer, C.G.; Horstmann, R.D.; Hill, A.V.We combined two tuberculosis genome-wide association studies from Ghana and The Gambia with subsequent replication in a combined 11,425 individuals. rs4331426, located in a gene-poor region on chromosome 18q11.2, was associated with disease (combined P = 6.8 x 10(-9), odds ratio = 1.19, 95% CI = 1.13-1.27). Our study demonstrates that genome-wide association studies can identify new susceptibility loci for infectious diseases, even in African populations, in which levels of linkage disequilibrium are particularly low.Item IL10 Haplotype Associated with Tuberculin Skin Test Response but Not with Pulmonary TB(PLoS ONE, 2009) Thye, T.; Browne, E.N.L.; Chinbuah, M.A.; Gyapong, J.O.; Osei, I.; Owusu-Dabo, E.; Brattig, N.W.; Niemann, S.; Rüsch-Gerdes, S.; Horstmann, R.D.; Meyer, C.G.Evidence from genetic association and twin studies indicates that susceptibility to tuberculosis (TB) is under genetic control. One gene implicated in susceptibility to TB is that encoding interleukin-10 (IL10). In a group of 2010 Ghanaian patients with pulmonary TB and 2346 healthy controls exposed to Mycobacterium tuberculosis, among them 129 individuals lacking a tuberculin skin test (PPD) response, we genotyped four IL10 promoter variants at positions 22849 , 21082 , 2819 , and 2592 and reconstructed the haplotypes. The IL10 low-producer haplotype 22849A/21082A/2819C/2592C, compared to the high-producer haplotype 22849G/21082G/2819C/2592C, occurred less frequent among PPD-negative controls than among cases (OR 2.15, CI 1.3–3.6) and PPD-positive controls (OR 2.09, CI 1.2–3.5). Lower IL-10 plasma levels in homozygous 22849A/21082A/2819C/2592C carriers, compared to homozygous 22849G/21082G/2819C/2592C carriers, were confirmed by a IL-10 ELISA (p = 0.016). Although we did not observe differences between the TB patients and all controls, our results provide evidence that a group of individuals exposed to M. tuberculosis transmission is genetically distinct from healthy PPD positives and TB cases. In these PPD-negative individuals, higher IL-10 production appears to reflect IL-10-dependent suppression of adaptive immune responses and sustained long-term specific anergy.Item MCP-1 promoter variant -362C associated with protection from pulmonary tuberculosis in Ghana, West Africa(Oxford University Press, 2009) Thye, T.; Nejentsev, S.; Intemann, C.D.; Browne, E.N.; Chinbuah, M.A.; Gyapong, J.; Osei, I.; Owusu-Dabo, E.; Zeitels, L.R.; Herb, F.; Horstmann, R.D.; Meyer, C.G.Current endeavour focuses on human genetic factors that contribute to susceptibility to or protection from tuberculosis (TB). Monocytes are crucial in containing Mycobacterium tuberculosis infection, and the monocyte chemoattractant protein-1 (MCP-1) cytokine plays a role in their recruitment to the site of infection. The G allele of the MCP-1 promoter polymorphism at position -2581 relative to the ATG transcription start codon has been described to be associated in Mexican and Korean TB patients with increased susceptibility to TB. We genotyped this and additional MCP-1 variants in sample collections comprising more than 2000 cases with pulmonary TB and more than 2300 healthy controls and 332 affected nuclear families from Ghana, West Africa, and more than 1400 TB patients and more than 1500 controls from Russia. In striking contrast to previous reports, MCP-1 -2581G was significantly associated with resistance to TB in cases versus controls [odds ratio (OR) 0.81, corrected P-value (P corr) = 0.0012] and nuclear families (OR 0.72, P corr = 0.04) and not with disease susceptibility, whereas in the Russian sample no evidence of association was found (P = 0.86). Our and other results do not support an association of MCP-1 -2581 with TB. In the Ghanaian population, eight additional MCP-1 polymorphisms were genotyped. MCP-1 -362C was associated with resistance to TB in the case-control collection (OR 0.83, P corr = 0.00017) and in the affected families (OR 0.7, P corr = 0.004). Linkage disequilibrium (LD) and logistic regression analyses indicate that, in Ghanaians, the effect results exclusively from the MCP-1 -362 variant, whereas the effect of -2581 may in part be explained by its LD with -362.Item MCP-1 promoter variant 2362C associated with protection from pulmonary tuberculosis in Ghana, West Africa(Oxford University Press, 2008) Thye, T.; Nejentsev, S.; Intemann, C.D.; Browne, E.N.; Chinbuah, M.A.; Gyapong, J.O.; Osei, I.; Owusu-Dabo, E.; Zeitels, L.R.; Herb, F.; Horstmann, R.D.; Meyer, C.G.Current endeavour focuses on human genetic factors that contribute to susceptibility to or protection from tuberculosis (TB). Monocytes are crucial in containing Mycobacterium tuberculosis infection, and the mono cytechemoattractant protein-1 (MCP-1) cytokine plays a role in their recruitment to the site of infection. The G allele of the MCP-1 promoter polymorphism at position 22581 relative to the ATG transcription start codon has been described to be associated in Mexican and Korean TB patients with increased susceptibility to TB. We genotyped this and additional MCP-1 variants in sample collections comprising more than 2000 cases with pulmonary TB and more than 2300 healthy controls and 332 affected nuclear families from Ghana, West Africa, and more than 1400 TB patients and more than 1500 controls from Russia. In striking contrast to previous reports, MCP-1 22581G was significantly associated with resistance to TB in cases versus controls [odds ratio (OR) 0.81, corrected P-value (Pcorr) 5 0.0012] and nuclear families (OR 0.72, Pcorr 5 0.04) and not with disease susceptibility, whereas in the Russian sample no evidence of association was found (P 50.86). Our and other results do not support an association of MCP-1 22581 with TB. In the Ghanaian population, eight additional MCP-1 polymorphisms were genotyped. MCP-1 2362C was associated with resistance to TB in the case–control collection (OR 0.83, Pcorr 5 0.00017) and in the affected families (OR 0.7, Pcorr 50.004). Linkage disequilibrium (LD) and logistic regression analyses indicate that, in Ghanaians, the effect results exclusively from the MCP-1 2362 variant, whereas the effect of 22581 may in part be explained by its LD with 2362.Item MCP1 haplotypes associated with protection from pulmonary tuberculosis(BMC Genetics, 2011) Intemann, C.D.; Thye, T.; Förster, B.; Owusu-Dabo, E.; Gyapong, J.O.; Horstmann, R.D.; Meyer, C.G.Background: The monocyte chemoattractant protein 1 (MCP-1) is involved in the recruitment of lymphocytes and monocytes and their migration to sites of injury and cellular immune reactions. In a Ghanaian tuberculosis (TB) case-control study group, associations of the MCP1 -362C and the MCP1 -2581G alleles with resistance to TB were recently described. The latter association was in contrast to genetic effects previously described in study groups originating from Mexico, Korea, Peru and Zambia. This inconsistency prompted us to further investigate the MCP1 gene in order to determine causal variants or haplotypes genetically and functionally. Results: A 14 base-pair deletion in the first MCP1 intron, int1del554-567, was strongly associated with protection against pulmonary TB (OR = 0.84, CI 0.77-0.92, Pcorrected = 0.00098). Compared to the wildtype combination, a haplotype comprising the -2581G and -362C promoter variants and the intronic deletion conferred an even stronger protection than did the -362C variant alone (OR = 0.78, CI 0.69-0.87, Pnominal = 0.00002; adjusted Pglobal = 0.0028). In a luciferase reporter gene assay, a significant reduction of luciferase gene expression was observed in the two constructs carrying the MCP1 mutations -2581 A or G plus the combination -362C and int1del554-567 compared to the wildtype haplotype (P = 0.02 and P = 0.006). The associated variants, in particular the haplotypes composed of these latter variants, result in decreased MCP-1 expression and a decreased risk of pulmonary TB. Conclusions: In addition to the results of the previous study of the Ghanaian TB case-control sample, we have now identified the haplotype combination -2581G/-362C/int1del554-567 that mediates considerably stronger protection than does the MCP1 -362C allele alone (OR = 0.78, CI 0.69-0.87 vs OR = 0.83, CI 0.76-0.91). Our findings in both the genetic analysis and the reporter gene study further indicate a largely negligible role of the variant at position -2581 in the Ghanaian population studied.Item No associations of human pulmonary tuberculosis with Sp110 variants(J. Med. Genet, 2007) Thye, T.; Browne, E.N.; Chinbuah, M.A.; Gyapong, J.O.; Osei, I.; Owusu-Dabo, E.; Niemann, S.; Rüsch-Gerdes, S.; Horstmann, R.D.; Meyer, C.G.Background: After a recent report on the role of the Ipr1 gene in mediating innate immunity in a mouse model of Mycobacterium tuberculosis infection, the human Ipr1 homologue, Sp110, was considered a promising candidate for an association study in human tuberculosis. Methods: In a sample of .1000 sputum positive, HIV negative West African patients with pulmonary tuberculosis and .1000 exposed, apparently healthy controls, we have genotyped 21 Sp110 gene variants that were either available from public databases, including HapMap data, or identified by DNA re-sequencing. Results: No significant differences in the frequencies of any of the 21 variants were observed between patients and controls. This applied also for HapMap tagging variants and the corresponding haplotypes, when including sliding window analyses with three adjacent variants, and when stratifying controls for positivity and negativity according to the results of intradermal tuberculin (purified protein derivative, PPD) skin tests. DNA re-sequencing revealed 13 novel Sp110 variants in the 59-UTR, exons, and adjacent intronic regions. Conclusions: Based on the results obtained in this case control study, the hypothesis that Sp110 variants and haplotypes might be associated with distinct phenotypes of human M tuberculosis infection is doubtful.Item Pulmonary tuberculosis: virulence of Mycobacterium africanum and relevance in HIV co-infection(Elsevier, 2008) Meyer, C.G.; Scarisbrick, G.; Niemann, S.; Browne, E.N.L.; Chinbuah, M.A.; Gyapong, J.O.; Osei, I.; Owusu-Dabo, E.; Kubica, T.; Rüsch-Gerdes, S.; Thye, T.; Horstmann, R.D.Although Mycobacterium africanum is being isolated in a significant proportion of cases of pulmonary tuberculosis in West Africa, its pathogenic potential remains a matter of discussion. Recent reports leave the question of whether M. africanum causes more severe pathology than M. tuberculosis or resembles opportunistic pathogens and might gain importance in the course of the HIV pandemic. Patients with pulmonary tuberculosis associated with M. africanum(nZ556) and M. tuberculosis (nZ1350) were studied in Ghana, West Africa, and compared regarding self-reported signs and symptoms, chest radiography, HIV status, mycobacterial drug resistance and mycobacterial clustering as determined by spoligotyping and IS6110 fingerprints. The rate of M. africanum infections was similar in HIV-positive (27%) and HIV-negative (30%) patients. M. africanum clustered less than M. tuberculosis (21% vs 79%; OR, 0.38; 95% CI, 0.3e0.5; p < 0.001) corresponding to its lower prevalence (29% vs 70%). Clinically and radiographically, no significant differences were found except that M. africanum caused lower-lobe disease less frequently than M. tuberculosis (OR, 0.39; 95% CI, 0.2e0.7; pcZ0.01), whereby this association applied to HIV-negative patients only. No difference in virulence, as assessed by the severity of radiological presentation, was found when the two M. africanum subtypes West African 1 andWest African 2 were compared. In the population studied, M. africanum closely resembled M. tuberculosis in pathology and cannot be considered an opportunistic pathogen.Item A structural variant of the human interferon-gamma gene(John Wiley & Sons, 2009) Thye, T.; Intemann, C.D.; Gyapong, J.O.; Horstmann, R.D.; Meyer, C.G.The first structural IFNG variant, G54D (c.287G>A, ss105106770), located in the second exon, was identified.Item Variant G57E of Mannose Binding Lectin Associated with Protection against Tuberculosis Caused by Mycobacterium africanum but not by M. tuberculosis(PLoS ONE, 2011-06) Thye, T.; Niemann, S.; Walter, K.; Homolka, S.; Intemann, C.D.; Chinbuah, M.A.; Enimil, A.; Gyapong, J.O.; Owusu-Dabo, E.; Rüsch-Gerdes, S.; Horstmann, R.D.; Ehlers, S.; Meyer, C.G.Structural variants of the Mannose Binding Lectin (MBL) cause quantitative and qualitative functional deficiencies, which are associated with various patterns of susceptibility to infectious diseases and other disorders. We determined genetic MBL variants in 2010 Ghanaian patients with pulmonary tuberculosis (TB) and 2346 controls and characterized the mycobacterial isolates of the patients. Assuming a recessive mode of inheritance, we found a protective association between TB and the MBL2 G57E variant (odds ratio 0.60, confidence interval 0.4–0.9, P 0.008) and the corresponding LYQC haplotype (Pcorrected 0.007) which applied, however, only to TB caused by M. africanum but not to TB caused by M. tuberculosis. In vitro, M.africanum isolates bound recombinant human MBL more efficiently than did isolates of M. tuberculosis. We conclude that MBL binding may facilitate the uptake of M. africanum by macrophages, thereby promoting infection and that selection by TB may have favoured the spread of functional MBL deficiencies in regions endemic for M. africanum