Interferon-gamma gene (T874A and G2109A) polymorphisms are associated with microscopy-positive tuberculosis.

Genetic susceptibility to tuberculosis includes several unknown yet different loci each contributing to a small extent. Intronic polymorphisms within the interferon-gamma (IFN-gamma) gene IFNG T+874A and IFNG G+2109A correlate with the IFN-gamma production in vitro, and the frequency of potential high IFN-gamma producers was previously reported by others to be lower in patients than in controls from Sicily. The aim of this study was to determine whether there is an association between polymorphisms in the IFN-gamma gene and predisposition to tuberculosis. We analysed two IFNG SNPs (T+874A and G+2109A) in patients (n = 253) hospitalized in Rijeka (Croatia) and controls (n = 519) from the same area. One-fifth of the controls were healthy contacts of the diseased, and the rest were blood donors. IFNG alleles, their predicted haplotypes or genotypes were not associated with disease susceptibility. Thus, we could not reproduce results from Sicilian case-control study. However, T/T+874 (possible high IFN-gamma producer) and +874A/A (putative low producer) genotypes were associated with microscopically positive-negative forms of disease. Haplotypes (T+874A and G+2109A) based on a prediction by software phase and subsequent genotype analysis corroborated these findings. Patients had significantly higher frequency of genotypes without T at +874 (AA/AA; AA/AG and AG/AG) in microscopy- or bacterial culture-positive groups compared with their negative counterparts. These data suggest an association with disease severity rather than susceptibility to tuberculosis in Croatian Caucasian population.

Interferon-gamma receptor-1 gene promoter polymorphisms (G-611A; T-56C) and susceptibility to tuberculosis.

We analysed frequencies of two single-nucleotide polymorphisms (SNP) in the interferon-gamma (IFN-gamma) receptor-1 (IFNGR1) gene promoter (G-611A, T-56C) in tuberculosis patients (n = 244) and compared them with controls (n = 521). These frequencies were not significantly different, whether analysed independently or as haplotypes. Because these SNP affect transcription, the results suggest that the expression of the IFNGR1 gene does not confer susceptibility to disease in patients from Croatia. Further analysis revealed a significant association between the protective (CA)(n) polymorphism (22 repeats, 192 FA(1)), located in the fifth intron of the IFNGR1 gene (+16682), and GT promoter haplotype (-611; -56) that showed the strongest expression capacity. In addition to this cis relationship, the (CA)(22) allele was correlated in trans with an IFN-gamma SNP (IFNG G + 2109A), which might affect the transcription of the IFNG gene. These results suggest that a particular combination of IFNG and IFNGR1 SNP might offer a better protection against tuberculosis in this population.

Interferon-gamma receptor-1 gene polymorphism in tuberculosis patients from Croatia.

Recent studies have indicated that the interleukin-12/interferon-gamma (IFN-gamma) axis is important in mycobacterial infection susceptibility. Using an intronic (CA)n polymorphic microsatellite marker within the IFN-gamma receptor-1 (IFNGR1) gene, we have compared the allelic frequencies of this marker in hospitalized tuberculosis patients (n = 120) with that of controls (n = 87) from Rijeka, Croatia. We identified 13 (CA)n alleles in the tuberculosis patients, whereas only 10 were found in the controls. A significant difference between one allelic marker and the control group was observed (P = 0.02, 95% confidence interval 0.14-0.94), suggesting a possible protective association. In contrast, several other allelic markers showed a trend towards association with the disease. We also found a trend towards an increased frequency in homozygosity of one allelic marker in patients (11.7%) as compared with controls (4.6%). We conclude that there is no evidence for disease association of the IFNGR1 gene marker in Mendelian-type (single-allele) inheritance. However, our results also suggest that unidentified allelic variations in the IFNGR1 gene might elevate or decrease the risk in this ethnic population, as a part of the multigenic predisposition to tuberculosis.

Cytokines in patients with lung cancer.

Lung cancer is one of the most common malignant diseases and is amongst the leading causes of death. Cell-mediated immune response and cytokines could play an important role in antitumour immunity. The aim of the study was to evaluate the cytokines', tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6, releasing capacity in patients with lung carcinoma and benign lung disease. A group of 41 patients were tested for the production of TNF-alpha, IL-1beta and IL-6 in bronchoalveolar lavage (BAL) and blood. The levels of cytokines in the lung cancer patients were: (1) in BAL - IL-6, 173 +/- 85 pg/ml; TNF-alpha, 170 +/- 116 pg/ml; and IL-1beta, 473 +/- 440 pg/ml; (2) in the blood - IL-6, 197 +/- 53 pg/ml; TNF-alpha, 311 +/- 202 pg/ml; and IL-1beta, 915 +/- 239 pg/ml. Alveolar macrophages of the patients with a lung cancer secreted significantly more cytokines, IL-6 (P = 0.0004) and IL-1beta (P = 0.0047), than alveolar macrophages of the patients with a nonmalignant lung cancer. However, significantly lower levels of cytokine production by the BAL cells were found in patients with small cell lung cancer. This production decreased further in phase IV of nonsmall cell lung cancer.

Clinical validation of bronchial hyperresponsiveness, allergy tests and lung function in the diagnosis of asthma in persons with dyspnea.

The aim of the study was to determine the most useful tests for decision making in the diagnosis of asthma in patients with dyspnea assessed by commonly used terms: sensitivity, specificity, positive and negative predictive values and diagnostic accuracy. In a group of 195 patients with dyspnea data were analyzed with respect to case histories and different diagnostic procedures: bronchial hyperresponsiveness (BHR), skin prick tests (SPT), total IgE, spirometry (FEV1), sputum eosinophils (SE) and blood eosinophilia (BE). Asthma was diagnosed in 141 subjects. The control group comprised 18 subjects. Sensitivity for BHR in asthma in subjects with dyspnea amounted to 97%, for SPT to 62%, while all other diagnostics were lower than 50%. Specificity was highest for SE (94%), and BHR (85%). Positive predictive value (PPV) in asthma was for BHR 94%, for SE 86%, for SPT 81%, for decreased FEV1 79%, total IgE 72% and BE 64%. The highest negative predictive value (NPV) was found for BHR (92%). Diagnostic accuracy was highest for BHR 93% and for SPT 62%, while all other tests were comparable or lower than 50%. It is not possible to conclude whether or not a person has asthma merely on the basis of data on skin sensitization to aeroallergens, total IgE, eosinophils or lung function tests. Bronchial hyperresponsiveness showed the highest values for sensitivity (97%), PPV (94%), NPV (92%) and accuracy (93%). The second most efficient test is the skin prick test, with PPV 81% and diagnostic accuracy 62%.