Association of blood lipid profiles and asthma: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Observational studies and meta-analyses have indicated associations between blood lipid profiles and asthma. However, the causal association is unknown. Therefore, this study investigated the causal relationship between blood lipid profiles and asthma using bidirectional Mendelian randomization analysis. METHODS AND MATERIALS: Our analyses were performed using individual data from the Taiwan Biobank and summary statistics from the Asian Genetic Epidemiology Network (AGEN). The causal estimates between all genetic variants, exposures of interest and asthma were calculated using an inverse-variance weighted method based on Taiwan Biobank data from 24,853 participants (mean age, 48.8 years; 49.8% women). Sensitivity analyses, including the weighted median, MR Egger regression, MR-PRESSO, mode-based estimate, contamination mixture methods, and leave-one-out analysis, were applied to validate the results and detect pleiotropy. RESULTS: In the inverse-variance weighted (IVW) analyses, we found evidence of a significant causal effect of an increased level of low-density lipoprotein cholesterol on asthma risk (ßIVW = 1.338, p = 0.001). A genetically decreased level of high-density lipoprotein cholesterol was also associated with asthma risk (ßIVW = -0.338, p = 0.01). We also found that an increased level of total cholesterol was associated with an increased risk of asthma (ßIVW = 1.343, p = 0.001). Several sensitivity analyses generated consistent findings. We did not find evidence to support the causality between asthma and blood lipid profiles in either direction. CONCLUSION: Our results supported the causal relationship between higher levels of LDL cholesterol and total cholesterol and lower levels of HDL cholesterol with an increased risk of asthma.

Increased di-(2-ethylhexyl) phthalate exposure poses a differential risk for adult asthma clusters.

BACKGROUND: DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are "non-atopic", lacking a clear etiology. METHODS: In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman's rank correlation coefficients, multiple logistic regression, and multinomial logistic regression. RESULTS: Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified. CONCLUSION: The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies.

Cluster analysis of phenotypes, job exposure, and inflammatory patterns in elderly and nonelderly asthma patients.

BACKGROUND: Asthma has been identified as different phenotypes due to various risk factors. Age differences may have potential effects on asthma phenotypes. Our study aimed to identify potential asthma phenotypes among adults divided by age as either younger or older than 65 years. We also compared differences in blood granulocyte patterns, occupational asthmagens, and asthma control-related outcomes among patient phenotype clusters. METHODS: We recruited nonelderly (<65 years old) (n = 726) and elderly adults (≥65 years old) (n = 201) with mild-to-severe asthma. We conducted a factor analysis to select 17 variables. A two-step cluster analysis was used to classify subjects with asthma phenotypes, and a discriminant analysis was used to verify the classification of cluster results. RESULTS: There were three clusters with different characteristics identified in both the nonelderly and elderly asthmatic adults. In the nonelderly patient group, cluster 2 (obese, neutrophilic phenotypes) had a 1.85-fold significantly increased risk of asthma exacerbations. Cluster 3 (early-onset, atopy, and smoker with an eosinophil-predominant pattern) had a 2.37-fold risk of asthma exacerbations and higher oral corticosteroid (OCS) use than cluster 1 (late-onset and LMW exposure with paucigranulocytic blood pattern). Among elderly patients, cluster 2 had poor lung function and more ex-smokers. Cluster 3 (early-onset, long asthma duration) had the lowest paucigranulocytic blood pattern percentages in the elderly group. CONCLUSIONS: The novelty of the clusters was found in age-dependent clusters. We identified three distinct phenotypes with heterogeneous characteristics, asthma exacerbations and medicine use in nonelderly and elderly asthmatic patients, respectively. Classification of age-stratified asthma phenotypes may lead to precise identification of patients, which provides personalized disease management.

Environmental risks and sphingolipid signatures in adult asthma and its phenotypic clusters: a multicentre study.

BACKGROUND: Adult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity. METHODS: Environmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case-control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables. FINDINGS: In the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28-3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108-0.311, p<0.05), but not with the accumulated levels of PM2.5 exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (p<0.001 and p<0.05, respectively), correlating with the levels of PAH (r=0.196, p<0.01) and metal exposure (r=0.202-0.323, p<0.05), respectively, and both correlating with circulating inflammatory markers (r=0.186-0.427, p<0.01). Analysis of six phenotypic clusters and those cases with comorbid type 2 diabetes mellitus (T2DM) revealed cluster-selective environmental risks and biosignatures. INTERPRETATION: These results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity.

MicroRNA-23a-3p Down-Regulation in Active Pulmonary Tuberculosis Patients with High Bacterial Burden Inhibits Mononuclear Cell Function and Phagocytosis through TLR4/TNF-α/TGF-ß1/IL-10 Signaling via Targeting IRF1/SP1.

The aim of this study is to explore the role of microRNAs (miR)-21/23a/146a/150/155 targeting the toll-like receptor pathway in active tuberculosis (TB) disease and latent TB infection (LTBI). Gene expression levels of the five miRs and predicted target genes were assessed in peripheral blood mononuclear cells from 46 patients with active pulmonary TB, 15 subjects with LTBI, and 17 non-infected healthy subjects (NIHS). THP-1 cell lines were transfected with miR-23a-3p mimics under stimuli with Mycobacterium TB-specific antigens. Both miR-155-5p and miR-150-5p gene expressions were decreased in the active TB group versus the NIHS group. Both miR-23a-3p and miR-146a-5p gene expressions were decreased in active TB patients with high bacterial burden versus those with low bacterial burden or control group (LTBI + NIHS). TLR2, TLR4, and interleukin (IL)10 gene expressions were all increased in active TB versus NIHS group. MiR-23a-3p mimic transfection reversed ESAT6-induced reduction of reactive oxygen species generation, and augmented ESAT6-induced late apoptosis and phagocytosis, in association with down-regulations of the predicted target genes, including tumor necrosis factor (TNF)-α, TLR4, TLR2, IL6, IL10, Notch1, IL6R, BCL2, TGF-ß1, SP1, and IRF1. In conclusion, the down-regulation of miR-23a-3p in active TB patients with high bacterial burden inhibited mononuclear cell function and phagocytosis through TLR4/TNF-α/TGF-ß1/IL-10 signaling via targeting IRF1/SP1.

Whole Genome DNA Methylation Analysis of Active Pulmonary Tuberculosis Disease Identifies Novel Epigenotypes: PARP9/miR-505/RASGRP4/GNG12 Gene Methylation and Clinical Phenotypes.

We hypothesized that DNA methylation patterns may contribute to the development of active pulmonary tuberculosis (TB). Illumina's DNA methylation 450 K assay was used to identify differentially methylated loci (DML) in a discovery cohort of 12 active pulmonary TB patients and 6 healthy subjects (HS). DNA methylation levels were validated in an independent cohort of 64 TB patients and 24 HS. Microarray analysis identified 1028 DMLs in TB patients versus HS, and 3747 DMLs in TB patients after versus before anti-TB treatment, while autophagy was the most enriched signaling pathway. In the validation cohort, PARP9 and miR505 genes were hypomethylated in the TB patients versus HS, while RASGRP4 and GNG12 genes were hypermethylated, with the former two further hypomethylated in those with delayed sputum conversion, systemic symptoms, or far advanced lesions. MRPS18B and RPTOR genes were hypomethylated in TB patients with pleural involvement. RASGRP4 gene hypermethylation and RPTOR gene down-regulation were associated with high mycobacterial burden. TB patients with WIPI2/GNG12 hypermethylation or MRPS18B/FOXO3 hypomethylation had lower one-year survival. In vitro ESAT6 and CFP10 stimuli of THP-1 cells resulted in DNA de-methylation changes of the PARP9, RASGRP4, WIPI2, and FOXO3 genes. In conclusions, aberrant DNA methylation over the PARP9/miR505/RASGRP4/GNG12 genes may contribute to the development of active pulmonary TB disease and its clinical phenotypes, while aberrant DNA methylation over the WIPI2/GNG12/MARPS18B/FOXO3 genes may constitute a determinant of long-term outcomes.

Defective formyl peptide receptor 2/3 and annexin A1 expressions associated with M2a polarization of blood immune cells in patients with chronic obstructive pulmonary disease.

BACKGROUND: Controversy exists in previous studies on macrophage M1/M2 polarization in chronic obstructive pulmonary disease (COPD). We hypothesized that formyl peptide receptor (FPR), a marker of efferocytosis and mediator of M1/M2 polarization, may be involved in the development of COPD. METHODS: We examined FPR 1/2/3 expressions of blood M1/M2a monocyte, neutrophil, natural killer (NK) cell, NK T cell, T helper (Th) cell, and T cytotoxic (Tc) cell by flowcytometry method in 40 patients with cigarette smoking-related COPD and 16 healthy non-smokers. Serum levels of five FPR ligands were measured by ELISA method. RESULTS: The COPD patients had lower M2a percentage and higher percentages of NK, NK T, Th, and Tc cells than the healthy non-smokers. FPR2 expressions on Th/Tc cells, FPR3 expressions of M1, M2a, NK, NK T, Th, and Tc cells, and serum annexin A1 (an endogenous FPR2 ligand) levels were all decreased in the COPD patients as compared with that in the healthy non-smokers. FPR1 expression on neutrophil was increased in the COPD patient with a high MMRC dyspnea scale, while FPR2 expression on neutrophil and annexin A1 were both decreased in the COPD patients with a history of frequent moderate exacerbation (≥ 2 events in the past 1 year). In 10 COPD patients whose blood samples were collected again after 1-year treatment, M2a percentage, FPR3 expressions of M1/NK/Th cells, FPR2 expression on Th cell, and FPR1 expression on neutrophil were all reversed to normal, in parallel with partial improvement in small airway dysfunction. CONCLUSIONS: Our findings provide evidence for defective FPR2/3 and annexin A1 expressions that, associated with decreased M2a polarization, might be involved in the development of cigarette smoking induced persistent airflow limitation in COPD.

Comprehensive risk factors, asthma control, and life quality pathways in adults with asthma: A structural equation modeling analysis.

OBJECTIVES: Previous studies reported that environmental factors, particularly the work environment, were related to quality of life (QoL) in patients with asthma. However, the pathway that links workplace and QoL in adults with asthma is still not clear. The aim of this study was to explore the comprehensive environmental factors, asthma control, and QoL pathways in patients with asthma. STUDY DESIGN AND SETTING: Two cohorts of patients with asthma were established, including a prospective phase cohort in 2006 and a cross-sectional phase cohort in 2012. The Asthma Control Test was used to determine the level of disease control, and QoL was assessed by using the Taiwanese version of an asthma quality-of-life questionnaire. In 2014, a structural equation model was applied to explore the pathways from the risk factors to QoL. RESULTS: The structural equation model for predicting QoL provided a good fit (χ(2) [degrees of freedom] = 43.81 [38]; root mean square error of approximation 0.021 [90% confidence interval, 0.001-0.044]) after combining the two cohorts. The wheeze frequency, allergic response frequency, parental asthma, and asthma control were directly associated with QoL. We found that patients who were obese and who worked in poor environments had increased work symptoms and wheeze frequency during the previous year in a cross-sectional phase cohort. However, we did not find that body mass index was a significant factor in a prospective cohort. The patients with obesity and with frequent work symptoms, which induced poor asthma control, were possible mechanisms in the pathway from workplace exposure to poor QoL in the observed adults with asthma in our combined data. CONCLUSION: Body mass index, the work environment, and the wheeze frequency should be considered when assessing asthma control and QoL in adult patients with asthma. Patients who reduce their body weight or avoid exposure to poor workplaces may find this useful for their asthma control and improvement of their QoL.

Protective effects of elafin against adult asthma.

BACKGROUND: Elafin inhibits serine proteases, such as human neutrophil elastase and proteinase 3, to prevent excessive damage during inflammation. However, the relationship between elafin and asthma is still unclear. Microarray technology was used to evaluate smoking- and asthma-related biomarkers in a discovery-driven manner. We identified candidate genes, e.g., proteinase inhibitor 3 (PI3), related to asthma and smoking from gene expression microarray data sets and evaluated their potential as biomarkers for asthma. METHODS: We used human genome microarray data sets from smoking- and asthma-related gene expression data sets and performed real-time quantitative polymerase chain reaction to measure and validate differences in gene expression. We also recruited adult patients with asthma and age- and sex-matched control patients who were administered a structured questionnaire and evaluated for lung function and plasma elafin levels, which are encoded by the PI3 gene. RESULTS: Six significantly altered candidate genes, PI3, protein kinase C iota, phosphoserine phosphatase, IQ motif-containing GTPase activating protein 1, interleukin 13 receptor α 1, and signal transducing adaptor molecule SH3 domain and ITAM motif 2, were identified from comparisons across the four asthma- and four smoking-related data sets included in this study. An in vitro study of human airway epithelial cells (A549) and a human monocytic cell line (THP-1) demonstrated that PI3 messenger RNA levels were significantly altered by nicotine exposure. Elafin concentration was significantly higher in control patients than in patients with asthma (p < 0.001). The plasma elafin concentration in the highest quartile (≥12.69 ng/mL) was inversely associated with asthma (adjusted odds ratio 0.122 [95% confidence interval, 0.053-0.278]) compared with the lowest quartile (<5.82 ng/mL) after adjusting for age, sex, smoking status, waist-to-hip ratio, percentage predicted forced expiratory volume in 1 second, cockroaches in the home, incense burning, and family history. CONCLUSION: Our study revealed that high elafin levels identified in smoking- and asthma-related microarray data sets and an epidemiologic study significantly reduced the risk of asthma. Further studies of elafin as a potential therapy for asthma are warranted.

Body composition modify the association between ambient particulate matter and lung function among asthma patients.

The effect of ambient PM10 and PM2.5 on lung function modified by body muscle and adipose tissue is not fully understood at present. Our aims were to investigate the association between seasonal average air pollutants and lung function in asthmatic patients modified by body composition indicators. In this cross-sectional study, we recruited 914 doctor-diagnosed asthmatic patients, and performed interaction and stratified analysis using the median values of total body muscle (TBM), total body fat (TBF), and percentage body fat (PBF) as well as body mass index (BMI) =25 as the cutoff points of the high/low body composition groups. The adjusted R2 values of the developed LUR models of PM2.5 and PM10 were 91.4% and 90.5% and also verified by cross-validation, respectively. After adjusting for confounding factors, we found that TBM significantly modified the association between PM10 and lung function among asthma patients (interaction P value <0.05). In the low TBM group, seasonal average concentrations of PM10 estimated by the LUR model increased by 10 µg/m3, and negative associations with lung function indicators were observed. For obese patients with BMI>25 and high TBF, the increase in PM10 was associated with the decrease in lung function. The asthma patients with obesity and low total body muscle were more susceptible to adverse effects of PM10 on lung function.

Association of baseline parameters with year 0 and year 1 acute exacerbations in male patients with chronic obstructive pulmonary disease.

OBJECTIVES: Acute exacerbations (AEs) of chronic obstructive pulmonary disease (COPD) can affect health status, hospitalization and readmission rates, and disease progression. This study aimed to identify independent markers associated with COPD AEs. METHODS: This study included male patients with COPD and collected data regarding their AEs and baseline clinical parameters. RESULTS: We included 149 male patients. Among them, 58 were included in the year 0 high-AE group and 91 in the low-AE group. Multivariate analysis revealed that the high-AE group had higher white blood cell count, lower serum albumin level, and post-bronchodilator (BD) forced expiratory volume in one second (FEV1) (%) with a combined receiver operating characteristic curve (ROC) of 0.721 (p < 0.001). Additionally, 34 patients were included in the year 1 high-AE group and 70 in the low-AE group (p < 0.001). Multivariate analysis revealed that the high-AE group had higher platelet count, positive asthma history, and lower pre-BD FEV1 (%) with a combined ROC of 0.782 (p < 0.001). CONCLUSION: In male patients with COPD, baseline white blood cell count, albumin level, and post-BD FEV1 (%) were correlated with year 0 AE; on the other hand, baseline platelet count, positive asthma history, and pre-BD FEV1 (%) were associated with year 1 AE.

Next generation sequencing reveals miR-431-3p/miR-1303 as immune-regulating microRNAs for active tuberculosis.

OBJECTIVES: RNA therapeutics is an emerging field that widens the range of treatable targets and would improve disease outcome through bypassing the antibiotic bactericidal targets to kill Mycobacterium tuberculosis (M.tb). METHODS: We screened for microRNA with immune-regulatory functions against M.tb by next generation sequencing of peripheral blood mononuclear cells, followed by validation in an independent cohort. RESULTS: Twenty three differentially expressed microRNAs were identified between 12 active pulmonary TB patients and 4 healthy subjects, and 35 microRNAs before and after 6-month anti-TB therapy. Enriched predicted target pathways included proteoglycan, HIF-1 signaling, longevity-regulating, central carbon metabolism, and autophagy. We validated miR-431-3p down-regulation and miR-1303 up-regulation accompanied with corresponding changes in their predicted target genes in an independent validation cohort of 46 active TB patients, 30 latent TB infection subjects, and 24 non-infected healthy subjects. In vitro experiments of transfections with miR-431-3p mimic/miR-1303 short interfering RNA in THP-1 cells under ESAT-6 stimuli showed that miR-431-3p and miR-1303 were capable to augment and suppress autophagy/apoptosis/phagocytosis of macrophage via targeting MDR1/MMP16/RIPOR2 and ATG5, respectively. CONCLUSIONS: This study provides a proof of concept for microRNA-based host-directed immunotherapy for active TB disease. The combined miR-431-3p over-expression and miR-1303 knock-down revealed new vulnerabilities of treatment-refractory TB disease.

The association between adult asthma and superoxide dismutase and catalase gene activity.

BACKGROUND: Adult asthma is caused by interaction effects of multiple genetic and environmental factors. Some studies have suggested that antioxidant enzyme activity and gene polymorphisms may play important roles in the context of asthma. Therefore, our study objectives were to investigate the association between asthma, antioxidant activities and the polymorphisms of manganese superoxide dismutase (Mn-SOD) or catalase (CAT). MATERIALS AND METHODS: A case-control study, for which we recruited 250 asthmatic adults and 250 age- and sex-matched controls. All subjects completed a questionnaire. Waist and hip circumference measurements, a lung function test and DNA genotyping were performed. In total, 50 incident cases and 50 matched controls who were non-smokers or had quit smoking for at least 1 year were selected in order to investigate SOD and CAT activity levels. RESULTS: In our study, we did not find a significant association between Mn-SOD Ala16Val, CAT C-262T and asthma. The level of SOD activity in new-onset asthma patients was significantly lower than in control subjects (p < 0.0005). The level of CAT activity in new-onset asthma patients was significantly higher than in control subjects (p < 0.0005). CONCLUSIONS: The levels of SOD and CAT activity were significantly related to adult asthma. SOD and CAT activity may be good tools to differentiate potential asthma sufferers. This would enable us to further investigate the mechanism of defective antioxidant enzymes in the context of asthma pathogenesis.

Risks of exposure to occupational asthmogens in atopic and nonatopic asthma: a case-control study in Taiwan.

RATIONALE: Asthma is often work-related and can be classified as atopic or nonatopic on the basis of its pathogenesis. Few studies have reported an association between exposure to occupational asthmogens and asthma with and without atopy. OBJECTIVES: We investigated, in adults with asthma, whether occupational exposure to asthmogens influenced the risk of having atopic or nonatopic asthma, and their level of lung function. METHODS: We recruited 504 hospital-based adults with current asthma, 504 community-based control subjects, and 504 hospital-based control subjects in southern Taiwan. Asthma with atopy was defined as having asthma in combination with an increase in total IgE (≥100 U/ml) or a positive Phadiatop test (≥0.35 Pharmacia arbitrary unit/L) (Pharmacia ImmunoCAP; Pharmacia, Uppsala, Sweden). Occupational exposure to asthmogens was assessed with an asthma-specific job exposure matrix. MEASUREMENTS AND MAIN RESULTS: We found a significant association between atopic asthma and exposure to high molecular weight asthmogens (adjusted odds ratio [AOR], 4.0; 95% confidence interval [CI], 1.8-8.9). Nonatopic asthma was significantly associated with exposure to low molecular weight asthmogens (AOR, 2.6; 95% CI, 1.6-4.3), including industrial cleaning agents and metal sensitizers. Agriculture was associated with both atopic and nonatopic asthma (AOR, 7.8; 95% CI, 2.8-21.8; and AOR, 4.1; 95% CI, 1.3-13.0, respectively). The ratio of FEV1 to FVC in the high-risk group was significantly lower than in the no-risk group (P = 0.026) in currently employed patients with asthma. CONCLUSIONS: In adults with asthma, occupational exposure to high and low molecular weight asthmogens appears to produce differential risks for atopic and nonatopic asthma.

Comparative analysis of the drug-drug interaction between immunosuppressants, safety and efficacy of rifabutin from rifampicin-based Anti-TB treatment in living donor liver transplant recipients with active tuberculosis.

BACKGROUND: The Interaction between anti-tuberculous and immunosuppressive drugs which may increase the risk of graft rejections is a major challenge in managing transplant recipients with tuberculosis (TB). Instead of rifampicin (RFM), most guidelines recommended the use of rifabutin (RFB) because of its reduced capacity to induce immunosuppressant metabolism while maintaining the same efficacy as RFM against TB. However, there has been no available data directly comparing the outcome of RFB from RFM-based anti-TB regimens in liver transplant patients with TB. This study aimed to compare the effects of RFB from RFM-based treatment in terms of the drug interaction with immunosuppressants, as well as the safety, efficacy and clinical outcomes of living donor liver transplant (LDLT) recipients with active TB. METHODS: A retrospective study was conducted on all adult LDLT recipients diagnosed with active TB from June 1994 to May 2016 that had concurrently and continuously received either RFB or RFM-based treatment and immunosuppressants. RESULTS: Twenty-two patients were included. Twelve (55%) patients were in the RFM group. Ten (45%) patients were in the RFB group. RFB group showed a lesser rate of immunosuppressant trough level reduction (20% vs 50%, p = 0.009) during TB treatment. There was no TB recurrence and no significant change in platelet or leukocyte count in either group. Acute cellular rejection (ACR), rate of TB-treatment completion and overall survival, rates were excellent and statistically similar in both groups. CONCLUSION: The use of RFB in LDLT recipients with active TB, had a lesser drug interaction than when RFM was used. However, RFB did not significantly reduced the rate of ACR. RFB and RFM are both effective and safe to use in LDLT recipients with active TB.

Epigenome-wide association study on asthma and chronic obstructive pulmonary disease overlap reveals aberrant DNA methylations related to clinical phenotypes.

We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). A total of 75 of 228 COPD patients were identified as ACO, which was independently associated with increased exacerbations. Microarray analysis identified 404 differentially methylated loci (DML) in ACO patients, and 6575 DML in those with rapid lung function decline in a discovery cohort. In the validation cohort, ACO patients had hypermethylated PDE9A (+ 30,088)/ZNF323 (- 296), and hypomethylated SEPT8 (- 47) genes as compared with either pure COPD patients or healthy non-smokers. Hypermethylated TIGIT (- 173) gene and hypomethylated CYSLTR1 (+ 348)/CCDC88C (+ 125,722)/ADORA2B (+ 1339) were associated with severe airflow limitation, while hypomethylated IFRD1 (- 515) gene with frequent exacerbation in all the COPD patients. Hypermethylated ZNF323 (- 296) / MPV17L (+ 194) and hypomethylated PTPRN2 (+ 10,000) genes were associated with rapid lung function decline. In vitro cigarette smoke extract and ovalbumin concurrent exposure resulted in specific DNA methylation changes of the MPV17L / ZNF323 genes, while 5-aza-2'-deoxycytidine treatment reversed promoter hypermethylation-mediated MPV17L under-expression accompanied with reduced apoptosis and decreased generation of reactive oxygen species. Aberrant DNA methylations may constitute a determinant for ACO, and provide a biomarker of airflow limitation, exacerbation, and lung function decline.

Toll-like receptor 2 gene polymorphisms, pulmonary tuberculosis, and natural killer cell counts.

BACKGROUND: To investigate whether the toll-like receptor 2 polymorphisms could influence susceptibility to pulmonary TB, its phenotypes, and blood lymphocyte subsets. METHODS: A total of 368 subjects, including 184 patients with pulmonary TB and 184 healthy controls, were examined for TLR2 polymorphisms over locus -100 (microsatellite guanine-thymine repeats), -16934 (T>A), -15607 (A>G), -196 to -174 (insertion>deletion), and 1350 (T>C). Eighty-six TB patients were examined to determine the peripheral blood lymphocyte subpopulations. RESULTS: We newly identified an association between the haplotype [A-G-(insertion)-T] and susceptibility to pulmonary TB (p = 0.006, false discovery rate q = 0.072). TB patients with systemic symptoms had a lower -196 to -174 deletion/deletion genotype frequency than those without systemic symptoms (5.7% vs. 17.7%; p = 0.01). TB patients with the deletion/deletion genotype had higher blood NK cell counts than those carrying the insertion allele (526 vs. 243.5 cells/microl, p = 0.009). TB patients with pleuritis had a higher 1350 CC genotype frequency than those without pleuritis (12.5% vs. 2.1%; p = 0.004). TB patients with the 1350 CC genotype had higher blood NK cell counts than those carrying the T allele (641 vs. 250 cells/microl, p = 0.004). TB patients carrying homozygous short alleles for GT repeats had higher blood NK cell counts than those carrying one or no short allele (641 vs. 250 cells/microl, p = 0.004). CONCLUSIONS: TLR2 genetic polymorphisms influence susceptibility to pulmonary TB. TLR2 variants play a role in the development of TB phenotypes, probably by controlling the expansion of NK cells.

Association of tumor necrosis factor-alpha-863C/A gene polymorphism with chronic obstructive pulmonary disease.

The aim of this study was to investigate genetic effects on the pathogenesis of chronic obstructive pulmonary disease (COPD). The study was conducted as a prospective case-control study in a medical center in southern Taiwan. The patient group consisted of 145 male patients with smoking-related COPD and a control group of 139 resistant smokers from July 2004 to September 2009. We compared allele and genotype frequencies of three tag single nucleotide polymorphisms (SNP) of the TNF-alpha gene promoter region at -308, -863, and -1031 in all subjects. We also analyzed the influence of each genetic variant on pulmonary function parameters, body mass index (BMI), serum TNF-alpha levels, and outcomes among heavy smokers with or without COPD. COPD patients had a significantly lower A allele frequency (9.7 vs. 15.1%, OR = 0.6, p = 0.048, false discovery rate q = 0.144) and a significantly lower A carrier genotype frequency (19.3 vs. 30.2%, OR = 0.52, p = 0.042, q = 0.135) than resistant smokers. The -863 CA genotype was associated with a better FEV(1)/FVC ratio (79 vs. 71.5%, p = 0.034), and higher BMI (24.9 vs. 23.6 kg/m(2), p = 0.048). In addition, COPD patients with the -1031 C carrier genotype had higher serum TNF-alpha levels (20.9 vs. 16.2 pg/ml, p = 0.01). BMI (hazard ratio = 0.84, 95% CI = 0.74-0.96, p = 0.008) was the only independent predictor for mortality. The TNF-alpha -863 A allele may confer a degree of resistance to the susceptibility to and muscle wasting of COPD among heavy smokers.

Blood M2a monocyte polarization and increased formyl peptide receptor 1 expression are associated with progression from latent tuberculosis infection to active pulmonary tuberculosis disease.

OBJECTIVES: This study aims to explore the role of M2a polarization and formyl peptide receptor (FPR) regulation in the reactivation of Mycobacterium tuberculosis (Mtb) infection. METHODS: M1/M2a monocyte percentage and FPR1/2/3 protein expression of blood immune cells were measured in 38 patients with sputum culture (+) active pulmonary TB disease, 18 subjects with latent TB infection (LTBI), and 28 noninfected healthy subjects (NIHS) using flow cytometry method. RESULTS: M1 percentage was decreased in active TB versus either NIHS or LTBI group, while M2a percentage and M2a/M1 percentage ratio were increased. FPR1 expression on M1/M2a, FPR2 expression on M1, and FPR3 expression of M1 were all decreased in active TB versus LTBI group, while FPR1 over FPR2 expression ratio on NK T cell was increased in active TB versus either NIHS or LTBI group. In 11 patients with active TB disease, M1 percentage became normal again after anti-TB treatment. In vitro Mtb-specific antigen stimulation of monocytic THP-1 cells resulted in M2a polarization in association with increased FPR2 expression on M2a. CONCLUSIONS: Increased M2a and decreased M1 phenotypes of blood monocyte may serve as a marker for active TB disease, while decreased FPR1 on blood monocyte may indicate LTBI status.