IFNG and IFNGR1 polymorphisms are associated with tuberculosis: a case-control study.

OBJECTIVE: Previous studies suggested that single-nucleotide polymorphisms (SNPs) of interferon gamma (IFNG) and its receptor IFNGR1 may be involved in the pathogenesis of tuberculosis (TB). We aimed to examine the association of IFNG gene polymorphisms with TB in the Tibetan population and use the machine learning method to establish a clinical prediction model of TB. PATIENTS AND METHODS: A total of 613 TB patients and 603 healthy controls were selected for the study. Associations between SNPs and TB were analyzed using logistic regression, adjusted for sex and age. Clinical data and SNPs were integrated to construct a TB prediction model using random forest (RF) machine learning. RESULTS: For IFNG, rs1861494 CT was a protective factor against TB compared with TT genotype (p = 0.010). The rs1861494 C allele was a protective factor for TB (p = 0.010). For IFNGR1, the rs3799488 C allele reduced the risk of TB by 30% (p < 0.001). rs9376267 CT (p = 0.005) and TT (p = 0.001) genotypes were protective factors for TB. Compared with the rs1327475 GG genotype, the frequency of the GA genotype in the case group significantly differed from the controls (p = 0.013). rs2234711 GA (p < 0.001), AA (p < 0.001) genotype and A (p < 0.001) alleles were also associated with TB. Finally, five markers are identified using the RF model. The area under the curve (AUC) reaches 0.6 in the training set and 0.59 in the test set. CONCLUSIONS: Our study found that IFNG and IFNGR1 gene polymorphisms were associated with TB in a Tibetan population. The results also demonstrate the potential of clinical-SNPs as diagnostic tools for TB.

Update meta-analysis of the CYP2E1 RsaI/PstI and DraI polymorphisms and risk of antituberculosis drug-induced hepatotoxicity: evidence from 26 studies.

WHAT IS KNOWN AND OBJECTIVE: Several studies have investigated the association of the CYP2E1 RsaI/PstI and/or DraI polymorphisms with susceptibility to antituberculosis drug-induced hepatotoxicity (ATDH), but the results have been inconsistent. Therefore, we performed a large meta-analysis to determine a more precise estimation of this relationship. METHODS: The PubMed, EMBASE, China National Knowledge Infrastructure and Chinese Biomedical Literature databases were systematically searched to identify relevant studies. Meta-analyses based on the entire population and subgroups were performed to examine the association between CYP2E1 polymorphisms and susceptibility to ATDH. The odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the associations. RESULTS AND DISCUSSION: Twenty-six studies with a total of 7423 participants were analysed. The overall ORs of relevant studies demonstrated that the CYP2E1 RsaI/PstI C1/C1 genotype was associated with an elevated risk of ATDH (OR = 1·32, 95% CI 1·03-1·69, P = 0·027), but for the DraI polymorphism there was no increase in risk (OR = 1·05, 95% CI 0·80-1·37, P = 0·748). In subgroup analyses of the RsaI/PstI polymorphism, significant results were found in East Asians, patients who used isoniazid + rifampicin + pyrazinamide + ethambutol and patients with twice the upper limit of normal as the minimum standard for defining ATDH. WHAT IS NEW AND CONCLUSION: This meta-analysis suggests that there is an increased risk of ATDH in individuals carrying the C1/C1 genotype of the CYP2E1 RsaI/PstI polymorphism. However, no association was found for the DraI polymorphism.

Associations of IL6 polymorphisms with lung function decline and COPD.

BACKGROUND: Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6. It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. METHODS: Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV(1)) over 5 years and baseline FEV(1) at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). RESULTS: In the LHS, three IL6 SNPs were associated with decline in FEV(1) (0.023< or =p< or =0.041 in additive models). Among them, the IL6_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_-174G/C, were associated with susceptibility to COPD (0.01< or =p< or =0.04 in additive genetic models). CONCLUSION: The results suggest that the IL6_-174G/C SNP is associated with a rapid decline in FEV(1) and susceptibility to COPD in smokers.

Selection of housekeeping genes for real-time PCR in atopic human bronchial epithelial cells.

The stability of housekeeping genes (HKGs) is critical when performing real-time quantitative PCR. To date, the stability of common HKGs has not been systematically compared in human airway epithelial cells (AEC) in normal and atopic subjects. Expression levels of 12 HKGs were measured in AECs from a cohort of 30 healthy atopic nonasthmatic or atopic asthmatic children. Gene expression stability was determined using three different Visual Basic for Applications applets (geNorm, NormFinder and BestKeeper). All 12 HKGs were expressed in AECs. However, the hypoxanthine ribosyltransferase and TATA-binding protein genes were excluded from further analysis due to low expression levels. The cyclophilin A gene was ranked the most stable by all three methods. The expression levels of the beta-actin and glyceraldehyde-3-phosphate dehydrogenase genes were significantly different between the three groups of patients, with atopic asthmatics showing the highest expression levels for both genes. The results suggest that the cyclophilin A gene is the most suitable housekeeping gene analysed for expression studies utilising uncultured bronchial airway epithelial cells from healthy and asthmatic children, and highlight the importance of validating housekeeping genes for each experimental model.

Association of genetic variations in the CSF2 and CSF3 genes with lung function in smoking-induced COPD.

Granulocyte-macrophage colony-stimulating factor (CSF), also known as CSF2, and granulocyte CSF, also known as CSF3, are important survival and proliferation factors for neutrophils and macrophages. The objective of the present study was to determine whether single nucleotide polymorphisms (SNPs) of CSF2 and CSF3 are associated with lung function in smoking-induced chronic obstructive pulmonary disease. In total, five SNPs of CSF2 and CSF3 were studied in 587 non-Hispanic white subjects with the fastest (n = 281) or the slowest (n = 306) decline of lung function selected from among continuous smokers in the National Heart, Lung, and Blood Institute Lung Health Study (LHS). These SNPs were also studied in 1,074 non-Hispanic white subjects with the lowest (n = 536) or the highest (n = 538) baseline lung function at the beginning of the LHS. An increase in the number of CSF3 -1719T alleles was significantly associated with protection against low lung function (odds ratio 0.73, 95% confidence interval 0.56-0.95), and was still significant after adjustment for multiple comparisons. There was also a significant association of a CSF3 haplotype with baseline levels of forced expiratory volume in one second. No association was found for CSF2 SNPs and lung function, nor was there evidence of epistasis. In conclusion, genetic variation in colony-stimulating factor 3 is associated with cross-sectionally measured lung function in smokers.

The curative effect of ALSS on 1-month mortality in AoCLF patients after 72 to 120 hours.

BACKGROUND: Hepatitis B virus (HBV)-related acute-on-chronic liver failure (AoCLF) is associated with a high mortality rate. An artificial liver support system (ALSS) creates a better environment for the self-regeneration of retained hepatocytes. AIM AND PATIENTS: We investigated the curative effect of ALSS on 1-month mortality at 72-120 h post-ALSS in 289 AoCLF patients. METHODS: Of the 289 patients, 117 who survived for at least 1 month post-ALSS comprised the survival group; the remaining cases who died within 1 month served as controls. The improvements in laboratory data and clinical syndromes at 72-120 h post-ALSS were compared with those at 24 h. RESULTS: Total bilirubin, international normalized ratio, and creatinine levels, and encephalopathy were significantly improved at 24 h post-ALSS in both the groups (p<0.05); however, these variables showed deterioration at 72-120 h; a rebound occurred in the nonsurvivors (p>0.05). The improvements in these variables in the nonsurvivors were considerably smaller than those in the survivors (p<0.05), particularly at 72-120 h. One-month mortality was more accurately predicted by the logistic regression model at 72-120 h than at 24 h. CONCLUSIONS: The prognosis of AoCLF patients was highly dependent on the improvement in encephalopathy, total bilirubin, international normalized ratio, and creatinine levels at 72-120 h post-ALSS. These variables are useful, therefore, as disease severity indexes to determine organ allocation priorities for liver transplant.

Polymorphisms of interleukin-10 and its receptor and lung function in COPD.

Interleukin (IL)-10 is a type-2 T-helper cell cytokine with a broad spectrum of anti-inflammatory actions. Inflammation plays an important role in the pathogenesis of chronic obstructive pulmonary disease. It was hypothesised that single nucleotide polymorphisms (SNPs) of the genes encoding IL-10 (IL10) and the alpha subunit of its receptor (IL10RA) are associated with changes in, or value of, forced expiratory volume in one second (FEV1) in smoking-induced chronic obstructive pulmonary disease. In total, eleven SNPs of IL10 and IL10RA were studied in 586 White subjects, selected from continuous smokers followed for 5 yrs in the Lung Health Study, who showed the fastest (n=280) and slowest (n=306) decline in FEV1. These 11 SNPs were also studied in 1,072 participants exhibiting the lowest (n=538) and highest (n=534) baseline FEV1 at the beginning of the Lung Health Study. No association was found in the primary analyses. Although a subgroup analysis showed that the IL-10 3368A allele was associated with a fast decline in FEV1, the association did not pass correction for multiple comparisons. No gene-gene interaction of IL10 with IL10RA was found. There was no association of polymorphisms of the genes encoding interleukin-10 and the alpha subunit of its receptor with the rate of decline in, or value of, forced expiratory volume in one second in smoking-induced chronic obstructive pulmonary disease.

Tumour necrosis factor and lymphotoxin A polymorphisms and lung function in smokers.

Genetic variants in the tumour necrosis factor (TNF) gene have been investigated in chronic obstructive pulmonary disease (COPD). However, there are many instances of nonreplication of these associations due to insufficient power or other factors. In this study, a large number of subjects were examined to elucidate whether genetic variations of TNF and/or lymphotoxin A (LTA), which is clustered with TNF, are associated with variations in lung function among smokers. The present authors designed two nested case-control studies in the National Heart, Lung, and Blood Institute Lung Health Study (LHS), which enrolled 5,887 smokers. The first design included continuous smokers who had the fastest (n = 279) and the slowest (n = 304) decline of lung function during the 5-yr follow-up period, and the second included the subjects who had the lowest (n = 533) and the highest (n = 532) post-bronchodilator % predicted forced expiratory volume in one second at the start of the LHS. Within the TNF and LTA region, 10 tagging single-nucleotide polymorphisms were selected and genotyped. Unlike the previous associations between TNF-308 and COPD in Asians, the current study found no association between either of the two phenotypes and the LTA and TNF polymorphisms. In conclusion, these results support the findings of previous studies in late-onset chronic obstructive pulmonary disease in Caucasian populations.

Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children.

We studied a cohort containing 368 children at high risk of developing atopy and atopic disorders and 540 parents of those children to investigate whether the IL13 Arg130Gln and C-1112 T polymorphisms were associated with these outcomes. We also investigated whether haplotypes consisting of any two polymorphisms of IL13 Arg130Gln, IL13 C-1112 T and IL4 C-589 T were associated with these phenotypes. In 288 white children, the IL13 130Gln allele was associated with atopy (RR=1.9, P=0.047), and with atopic dermatitis (RR=2.5, P=0.014). The associations were confirmed using a family-based test of association (P=0.027 and 0.030, respectively) in all subjects. In white subjects there were associations of haplotypes consisting of IL13 Arg130Gln and IL4 C-589 T with atopic dermatitis (P=0.006) and with atopy (P=0.009). Our data suggest that the IL13 Arg130Gln polymorphism and haplotypes consisting of IL13 Arg130Gln and IL4 C-589 T were associated with the development of atopy and atopic dermatitis at 24 months of age.

N-NO bond dissociation energies of N-nitroso diphenylamine derivatives (or analogues) and their radical anions: implications for the effect of reductive electron transfer on N-NO bond activation and for the mechanisms of NO transfer to nitranions

The heterolytic and homolytic N-NO bond dissociation energies [i.e., deltaHhet(N-NO) and deltaHhomo(N-NO)] of 12 N-nitroso-diphenylamine derivatives (1-12) and two N-nitrosoindoles (13 and 14) in acetonitrile were determined by titration calorimetry and from a thermodynamic cycle, respectively. Comparison of these two sets of data indicates that homolysis of the N-NO bonds to generate NO* and nitrogen radical is energetically much more favorable (by 23.3-44.8 kcal/mol) than the corresponding heterolysis to generate a pair of ions, giving hints for the driving force and possible mechanism of NO-initiated chemical and biological transformations. The first (N-NO)-* bond dissociation energies [i.e., deltaH(N-NO)-* and deltaH'(N-NO)-*] of radical anions 1-*-14-* were also derived on the basis of appropriate cycles utilizing the experimentally measured deltaHhet(N-NO) and electrochemical data. Comparisons of these two quantities with those of the neutral N-NO bonds indicate a remarkable bond activation upon a possible one-electron transfer to the N-NO bonds, with an average bond-weakening effect of 48.8 +/- 0.3 kcal/mol for heterolysis and 22.3 +/- 0.3 kcal/mol for homolysis, respectively. The good to excellent linear correlations among the energetics of the related heterolytic processes [deltaHhet(N-NO), deltaH(N-NO)-*, and pKa(N-H)] and the related homolytic processes [deltaHhomo(N-NO), deltaH'(N-NO)-*, and BDE(N-H)] imply that the governing structural factors for these bond scissions are similar. Examples illustrating the use of such bond energetic data jointly with relevant redox potentials for analyzing various mechanistic possibilities for nitrosation of nitranions are presented.