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Ming-Gui Wang,1,* Wei-Wei Huang,1,* Yu Wang,1 Yun-Xia Zhang,1 Miao-Miao Zhang,1 Shou-Quan Wu,1 Andrew J Sandford,2 Jian-Qing He1 1Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2Centre for Heart Lung Innovation, University of British Columbia and St. Paul’s Hospital, Vancouver, BC, Canada *These authors contributed equally to this work Background: Tobacco smoking is a risk factor for tuberculosis but little is known about the relationship between tobacco smoking and drug-resistant tuberculosis (DR-TB). We undertook a systematic review and meta-analysis to quantitatively assess the association between DR-TB and tobacco smoking.Methods: We searched for relevant studies in the Ovid MEDLINE, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, WANFANG, and WEIPU databases from inception to September 1, 2017. Results were expressed as odds ratios (ORs) with accompanying 95% CIs, and subgroup analyses were performed by study design, smoking type, DR-TB type, and multivariate analysis.Results: Thirty-three studies related to tobacco smoking and DR-TB were included. We found substantial evidence that tobacco smoking is associated with an increased risk of DR-TB (OR 1.57, 95% CI 1.33–1.86). Associations were also found in subgroup analyses: for multidrug-resistant tuberculosis (OR 1.49, 95% CI 1.19–1.86) and for any DR-TB (OR 1.70, 95% CI 1.3–2.23); the pooled OR was 1.45 (95% CI 1.11–1.90) for current smoking, 2.25 (95% CI 1.46–3.47) for past smoking, and 1.56 (95% CI 1.22–1.98) for smoking history; and similar ORs were also observed in study design and multivariate analysis subgroup analysis.Conclusion: This study demonstrated that tobacco smoking is an independent risk factor for DR-TB. Keywords: tobacco smoking, drug-resistant tuberculosis, multidrug-resistant tuberculosis, MDR-TB, meta-analysis

Background: Chronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury.Objectives: We hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease.Methods: In a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype.Measurements and Main Results: A total of 440 subjects with CF participated in the study (51% male; mean [+/- SD] age, 26 +/- 11 yr; mean FEV(1), 62 +/- 28% predicted). In the total population, there was a trend toward an association between GCLC genotypes and CF lung disease (linear regression coefficient [SEM], 1.68 [1.0]; p = 0.097). In the stratified analysis, there was a highly significant association between GCLC genotype and CF lung function in subjects with a milder CFTR genotype (linear regression coefficient [SEM], 5.5 (1.7); p = 0.001).Conclusions: In patients with CF with a milder CFTR genotype, there is a strong association between functional polymorphisms of the GCLC gene and CF lung disease severity. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: To assess the association between socioeconomic status (SES) and short-acting (SA) beta-agonist use, controlling for asthma severity. DESIGN: Cross-sectional study. SETTING: Vancouver, BC, Canada. PARTICIPANTS: Two hundred two asthmatics between 19 years and 50 years of age and residing in the greater Vancouver regional district. MEASUREMENTS: The quantity of SA beta-agonist used in the previous year was collected by self-report; pulmonary function and beta-receptor genotype were measured on each participant. SES was measured at both the individual and population levels. Five methods of adjustment for asthma severity were used, as follows: the Canadian Asthma Consensus Guidelines, three previously developed asthma-severity scores, and forward stepwise multiple regression modeling. Polychotomous logistic regression was used to assess all relationships. RESULTS: Independent of the method used to measure SES or adjust for asthma severity, lower SES was consistently and significantly associated with the use of greater amounts of SA beta-agonist. Adjusting for severity using the multivariate model explained the most variance of SA beta-agonist use (R(2) adjusted, 0.35 to 0.37). In this model, social assistance recipients were more likely to use greater amounts of SA beta-agonist (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.7 to 6.5). An inverse relationship between SA beta-agonist use and both annual household income (> $50,000; OR, 0.28; 95% CI, 0.13 to 0.60; and $20,000 to $50,000; OR, 0.44; 95% CI, 0.21 to 0.96; relative to <$20,000) and education (completing a bachelor's degree vs no formal education; OR, 0.25; 95% CI, 0.14 to 0.71). Participants living in a neighborhood with higher median household income (OR, 0.91; 95% CI, 0.84 to 0.98 per $1,000 increase) or a higher prevalence of having attained a bachelor's degree (OR, 0.96; 95% CI, 0.84 to 0.98 per 1% increase) were also less likely use greater amounts of SA beta-agonist. Results were consistent for neighborhood unemployment rate. CONCLUSIONS: The social gradient in asthma-related outcomes may be at least partially attributable to poorer asthma control in lower-SES asthmatics. [ABSTRACT FROM AUTHOR]

We studied glutathione S-transferase (GST) polymorphisms in 1,098 whites with the lowest (n = 544, FEV(1) % predicted mean +/- SEM = 62.6 +/- 0.1) and the highest (n = 554, FEV(1) % predicted mean +/- SEM = 91.8 +/- 0.1) lung function at the beginning of the Lung Health Study. Homozygosity for GSTP1 105Val was significantly more frequent in the low- than in the high-function group (13.2 vs. 9.3%) (odds ratio = 1.69, 95% confidence interval [CI] = 1.11-2.61, p = 0.016), after adjustment for confounding variables. Subjects with 105Val homozygotes had higher rates of lung function decline in the high-function group (p = 0.017). The frequencies of GSTM1, GSTT1 null genotypes were similar between the high- and low-function groups, but subjects with the GSTT1 null genotype had a faster decline of lung function in the low-function group (p = 0.032). In addition, there was a significant interaction of GSTT1 genotype and pack-years on lung function. When comparing individuals with GSTT1 null genotype with wild type, the adjusted odds ratio was 3.49 (95% CI, 1.48-8.39, p = 0.005) in mild smokers (< or = 25 pack years). We conclude that GST genotypes are risk factors for rapid decline or low lung function in smokers with mild to moderate airflow obstruction. [ABSTRACT FROM AUTHOR]

Background: Proteinase-activated receptor 2 (PAR-2) is a G-protein coupled receptor associated with many inflammatory diseases, including asthma. We have shown an association between PAR-2 expression in peripheral blood monocytes and asthma severity as well as blood PAR-2 mRNA level and lung function. Since F2RL1 (the gene encoding PAR-2) polymorphisms affect PAR-2 expression, we hypothesize they may affect asthma severity., Methods: We recruited 76 subjects with asthma of varying severity and collected clinical (FEV 1 [% predicted], FEV 1 /FVC, IgE) and immunological (PAR-2 mRNA, blood eosinophils) disease parameters. We also genotyped these individuals for 3 F2RL1 SNPs (-45C/T, -149C/G, c.621C/T)., Results: We found that the F2RL1 SNP "C" allele of -45C/T (rs1529505) was associated with PAR-2 mRNA and blood eosinophils. F2RL1 SNP c.621C/T (rs631465) was associated with PAR-2 mRNA. The F2RL1 SNP -149C/G (rs2242991) had no association with any of the parameters studied. This study identified one F2RL1 SNP rs1529505 is associated with parameters of asthma, but not asthma severity., Conclusion: Larger studies are needed to further elucidate the role of PAR-2 in the pathophysiology of asthma and the influence of genetic variation., (© 2024. The Author(s).)

Allergic rhinitis (AR) is characterized by an early-phase response (EPR), and in a subgroup of individuals, a late-phase response (LPR). We sought to investigate polymorphisms in cholinergic synapse pathway genes, previously associated with late-asthmatic responses, in the LPR. Twenty healthy participants and 74 participants with AR underwent allergen exposure using the Environmental Exposure Unit. Allergic participants were sub-phenotyped using self-reported nasal congestion scores; congestion is the predominant symptom experienced during the LPR. Acute congestion (AC, n = 36) participants developed only an EPR, while persistent congestion (PC, n = 38) participants developed both allergic responses. We interrogated blood samples collected before allergen exposure with genotyping and gene expression assays. Twenty-five SNPs located in ADCY3, AKT3, CACNA1S, CHRM3, CHRNB2, GNG4 , and KCNQ4 had significantly different allele frequencies ( P < 0.10) between PC and AC participants. PC participants had increased minor allele content ( P = 0.009) in the 25 SNPs compared to AC participants. Two SNPs in AKT3 were associated with gene expression differences (FDR < 0.01) in PC participants. This study identified an association between the LPR and polymorphisms in the cholinergic synapse pathway genes, and developed a novel method to sub-phenotype AR using self-reported nasal congestion scores., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Samra, Rajasekaran, Sandford, Ellis and Tebbutt.)

Background: Obstructive sleep apnea (OSA) patients are at increased risk of cardiovascular disease (CVD). Cell adhesion molecules (CAM) are increased in OSA and CAM are also implicated in the development of CVD., Research Question: Do CAM (ICAM-1, VCAM-1 and E-selectin) have prognostic value in identifying risk of cardiovascular events in OSA?, Study Design and Methods: Patients with suspected OSA referred for a polysomnogram provided a fasting blood sample. Plasma levels of ICAM-1, VCAM-1 and E-selectin were determined by multiplex Luminex Assay (Milliporesigma ON, Canada). Cardiovascular events were determined by deterministic linkage to provincial health databases., Results: 418 patients were included in the analysis. Mostly male (68.2%), mean age of 50.7 yrs, median AHI 16.5 events/hour, and mean BMI of 31.7 kg/m2. 36 cardiovascular events occurred in 8-yrs of follow up. Higher levels of ICAM-1 were associated with developing CVD (HR = 3.65 95% CI 1.40-9.53, 2nd and 3rd tertiles vs. 1st tertile), including in patients with OSA (HR = 3.1 95% CI 1.16-8.25). E-selectin was significantly associated with cardiovascular events in patients with moderate to severe OSA (HR = 3.31 95% CI 0.94-11.72, 2nd and 3rd tertiles vs. 1st tertile) but not in patients without moderate to severe OSA (HR = 0.67 95% CI 0.19-2.38), p-value for interaction = 0.07., Interpretation: In a suspected OSA cohort, patients with higher levels of ICAM-1 (>816 ng/ml) were significantly more likely to experience a cardiovascular event within 8 years after PSG. In moderate to severe OSA patients, a higher E-selectin (>36.4 ng/ml) was significantly associated with cardiovascular events., Competing Interests: The authors have declared no competing interests exist.

Background: Nuclear transcription factor erythroid 2 p45-related factor 2 (Nrf2), encoded by NFE2L2 , functions as a key transcription factor and regulates expression of antioxidant genes. Our study aimed to investigate the association of single nucleotide polymorphisms of NFE2L2 with tuberculosis (TB) and latent tuberculosis infection (LTBI) and the underlying causal mechanisms., Methods: 1950 unrelated Chinese Han participants were included in our two independent study groups. Five tag polymorphisms were selected and genotyped. The functional effects of the rs13005431 polymorphism were confirmed by dual-luciferase reporter assays and mRNA level comparisons., Results: Rs13005431&#95;C and rs2364723&#95;G were associated with increased TB susceptibility ( P = 0.010 and P = 0.041) after adjustment for confounding factors. rs6726395&#95;A was associated with increased risk of active TB ( P =0.035) in a comparison with the LTBI group. The frequency of haplotype rs1049751- rs13005431 AC was higher in the TB group ( P =0.013), while frequency of haplotype AT was higher in the healthy control group ( P =0.025). The luciferase activity of a plasmid with the rs13005431C-promoter was significantly lower than that of the rs13005431T-promoter. In addition, neutrophils with the CC/TC genotypes which were activated by GM-CSF showed a decreased level of NFE2L2 mRNA when compared with the rs13005431 TT genotype., Conclusions: Our study suggests that allele C of rs13005431 might increase the susceptibility to TB by down-regulating the transcriptional activity of NFE2L2 ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ji, Zhang, Liu, Wu, Wang, Chen, Sandford and He.)

Chronic obstructive pulmonary disease (COPD) is a disorder of accelerated lung aging. Multiple pieces of evidence support that the aging biomarker short telomeres, which can be caused by mutations in telomerase reverse transcriptase (TERT), contribute to COPD pathogenesis. We hypothesized that short telomere risk-associated single nucleotide polymorphisms (SNPs) in TERT, while not able to drive COPD development, nonetheless modify the disease presentation. We set out to test the SNP carrying status in a longitudinal study of smokers with COPD and found that rapid decline of FEV1 in lung function was associated with the minor allele of rs61748181 (adjusted odds ratio 2.49, p = 0.038). Biochemical evaluation of ex vivo engineered human cell models revealed that primary cells expressing the minor allele of rs61748181 had suboptimal telomere length maintenance due to reduced telomerase catalytic activity, despite having comparable cell growth kinetics as WT-TERT expressing cells. This ex vivo observation translated clinically in that shorter telomeres were found in minor allele carriers in a sub-population of COPD patients with non-declining lung function, over the 5-year period of the longitudinal study. Collectively, our data suggest that functional TERT SNPs with mild catalytic defects are nonetheless implicated in the clinical presentation of COPD.

Purpose: To investigate the relationship between obstructive sleep apnea (OSA) severity, body mass index (BMI), and circulating levels of inflammatory adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin)., Methods: A cross-sectional clinical cohort study on all consecutive adults referred to the University of British Columbia (UBC) Sleep Laboratory for a polysomnogram (PSG) for suspected OSA provided a morning blood sample. Samples were analyzed with multiplex immune assay (MilliporeSigma, CA) to assess the levels of adhesion molecules., Results: 488 patients were studied; the majority were male (68%) with a mean age of 50 yrs, mean AHI of 23 events/hour, and mean BMI of 32 kg/m 2 . In multivariable linear regression models, all three adhesion molecules were significantly associated with BMI (E-selectin p < 0.0001; ICAM-1 p = 0.0007; VCAM-1 p = 0.0003). However, only E-selectin was independently associated with AHI (p = 0.02); there was no significant interaction between AHI and BMI for E-selectin (p = 0.33)., Conclusions: Although all three adhesion molecules were associated with BMI, only E-selectin was independently associated with OSA severity. Future studies are needed to determine the clinical significance of the relationship between E-selectin and OSA.

Background: As a main line of defense of the respiratory tract, the airway epithelium plays an important role in the pathogenesis of asthma. CDHR3 and EMSY were reported to be expressed in the human airway epithelium. Although previous genome-wide association studies found that the two genes were associated with asthma susceptibility, similar observations have not been made in the Chinese Han population., Methods: A total of 300 asthma patients and 418 healthy controls unrelated Chinese Han individuals were enrolled. Tag-single nucleotide polymorphisms (Tag-SNPs) were genotyped and the associations between SNPs and asthma risk were analyzed by binary logistic regression analysis., Results: After adjusting for confounding factors, the A allele of rs3847076 in CDHR3 was associated with increased susceptibility to asthma (OR = 1.407, 95% CI: 1.030-1.923). For the EMSY gene, the T alleles of both rs2508746 and rs12278256 were related with decreased susceptibility to asthma (additive model: OR = 0.718, 95% CI: 0.536-0.961; OR = 0.558, 95% CI: 0.332-0.937, respectively). In addition, the GG genotype of rs1892953 showed an association with increased asthma risk under the recessive model (OR = 1.667, 95% CI: 1.104-2.518) and the GATCTGAGT haplotype in EMSY was associated with reduced asthma risk (P = 0.037)., Conclusions: This study identified novel associations of rs3847076 in CDHR3, as well as rs1892953, rs2508746 and rs12278256 in EMSY with adult asthma susceptibility in the Chinese Han population. Our observations suggest that CDHR3 and EMSY may play important roles in the pathogenesis of asthma in Chinese individuals. Further study with larger sample size is needed.

Background: Tuberculosis (TB) is an infectious disease, caused by mycobacterium tuberculosis infection, which is associated with oxidative stress and the induction of host antioxidants to counteract this response. The heme oxygenase-1 (HO-1) single nucleotide polymorphisms have been reported to be associated with many critical diseases. Our purpose was to investigate the association of HO-1 single nucleotide polymorphisms with the susceptibility to tuberculosis in Chinese Han population., Methods: A case-control study was performed on Chinese Han population, and a group of 638 TB patients was compared to 610 healthy controls. Three single nucleotide polymorphisms (SNPs) including rs2071746, rs5995098, and rs8140669 were genotyped using the MassARRAY platform. The genotype frequency was compared between TB patients and healthy controls. The association between the three genetic models of the three SNPs and TB risk was further investigated., Results: The results showed that, in the case of additive model, there was significant difference of the genotype frequencies of SNP rs8140669 between the TB patients and control groups (P = .038). In the case of dominant model, the genotype frequencies of SNP rs8140669 may have difference between the two cohorts (P = .051), while the allele frequency and genotype distribution for other two SNPs showed no significant difference between the two groups (P > .05)., Conclusion: HO-1 polymorphism was associated with TB susceptibility in Chinese Han population., (© 2020 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Background: Cystic fibrosis (CF) is characterized by a progressive decline in lung function due to airway obstruction, infection, and inflammation. CF patients are particularly susceptible to respiratory infection by a variety of pathogens, and the inflammatory response in CF is dysregulated and prolonged. BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are proteins expressed in the upper airways that may have innate immune activity. We previously identified polymorphisms in the BPIFA1/BPIFB1 region associated with CF lung disease severity., Methods: We evaluated whether the BPIFA1/BPIFB1 associations with lung disease severity replicated in individuals with CF participating in the International CF Gene Modifier Consortium (n = 6,365). Furthermore, we investigated mechanisms by which the BPIFA1 and BPIFB1 proteins may modify lung disease in CF., Results: The association of the G allele of rs1078761 with reduced lung function was replicated in an independent cohort of CF patients (p = 0.001, n = 2,921) and in a meta-analysis of the full consortium (p = 2.39x10-5, n = 6,365). Furthermore, we found that rs1078761G which is associated with reduced lung function was also associated with reduced BPIFA1, but not BPIFB1, protein levels in saliva from CF patients. Functional assays indicated that BPIFA1 and BPIFB1 do not have an anti-bacterial role against P. aeruginosa but may have an immunomodulatory function in CF airway epithelial cells. Gene expression profiling using RNAseq identified Rho GTPase signaling pathways to be altered in CF airway epithelial cells in response to treatment with recombinant BPIFA1 and BPIFB1 proteins., Conclusions: BPIFA1 and BPIFB1 have immunomodulatory activity and genetic variation associated with low levels of these proteins may increase CF lung disease severity., Competing Interests: The authors have declared that no competing interests exist.

Background: The Abbott RealTime MTB (Abbott-RT) and Abbott RealTime MTB RIF/INH Resistance (Abbott-RIF/INH) assays have been introduced for the detection of tuberculosis (TB) and drug-resistant tuberculosis (DR-TB). We performed a systematic review and meta-analysis to assess the accuracy of Abbott-RT and Abbott-RIF/INH for the detection of TB and DR-TB., Methods: The Ovid MEDLINE, EMBASE, Cochrane and Web of Science databases were searched to identify eligible articles for the systematic review. The pooled analyses were calculated with a bivariate model. Hierarchical summary receiver operating characteristic curves and the area under the curve (AUC) were used to summarize overall diagnostic performance. Deeks' test was performed to evaluate potential publication bias., Results: For the Abbott-RT assay, 9 studies including 3, 640 patients met the study criteria. The pooled sensitivity of Abbott-RT for detecting TB was 0.96 (95% CI: 0.88-0.99) and specificity was 0.97 (95% CI: 0.93-0.99). For DR-TB, four studies were included to evaluate the diagnosis accuracy of Abbott-RIF/INH. The pooled sensitivity was 0.88 (95% CI, 0.82-0.93) and specificity was 0.99 (95% CI, 0.96-0.99). No publication bias was found., Conclusion: Both Abbott-RT and Abbott-RIF/INH assays have good sensitivity, specificity and accuracy for the diagnosis of TB and DR-TB., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A combination therapy of multiple drugs including isoniazid, rifampicin, ethambutol and pyrazinamide has been proven to be an effective option for the vast majority of tuberculosis (TB) patients. However, various adverse drug reactions (ADRs) limit its merit, with anti-TB drug-induced hepatotoxicity (ATDH) being a common and sometimes severe ADR. This study aimed to investigate the association between polymorphisms in two nuclear receptor genes, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and the risk of ATDH in a Chinese population. Subjects with or without hepatotoxicity during anti-TB treatment were recruited. DNA was extracted from peripheral blood and genotypes of the selected single nucleotide polymorphisms (SNPs) were determined by using the improved multiplex ligation detection reaction technique. Three genetic models (additive, dominant, and recessive) as well as haplotype, SNP-SNP interaction analyses were used to evaluate the genetic risk of ATDH. A total of 502 subjects (203 ATDH and 299 non-ATDH) were enrolled. The results showed that the minor allele of rs7643645 and the H0010001 haplotype in PXR were associated with decreased risk of ATDH, suggesting that drug-metabolizing enzymes regulated by PXR are involved in the pathogenesis of ATDH. More studies are required to verify this result.

Background: The Myosin Heavy Chain 15 gene ( MYH15 ) is expressed in the airway epithelium and variants in the gene have been associated with airway responsiveness. The aim of this study was to perform the first investigation of MYH15 polymorphisms in relation to asthma susceptibility., Methods: A total of 410 asthma patients and 418 controls from the Chinese Han population were enrolled in the study. Tag-single nucleotide polymorphisms were genotyped and associations between the polymorphisms and asthma risk were analyzed by logistic regression analysis adjusting for confounding factors. Dual-luciferase reporter gene analysis was performed to detect allele-dependent promoter activity of MYH15 variants in HEK293 cells., Results: The A allele of rs9288876 decreased risk of asthma (allelic model: OR=0.808, 95% CI: 0.658-0.993, additive model: OR=0.747, 95% CI: 0.588-0.947, dominant model: OR=0.693, 95% CI: 0.502-0.955). The G alleles of both rs7635009 and rs1454197 were associated with decreased risk of asthma under the additive model (OR=0.779, 95% CI: 0.618-0.981 and OR=0.756, 95% CI: 0.600-0.953, respectively). rs9288876 allele A was associated with higher luciferase activity than allele T ( P <0.001). The luciferase activity of rs7635009 allele A was lower than allele G ( P =0.001), while rs1454197 allele T had lower luciferase activity than allele G ( P <0.001)., Conclusion: This is the first study to report the association of MYH15 gene polymorphisms with asthma. Polymorphisms of rs9288876, rs7635009, and rs1454197 altered transcriptional regulation of MYH15 and may be functional variants conferring susceptibility to asthma. Further study with larger sample size in different ethnic populations is needed.

Background: Toll-like receptor 1 (TLR1) and TLR6 play important roles in the innate immune response against Mycobacterium tuberculosis (M.TB) via interactions with TIR domain-containing adaptor protein (TIRAP) and myeloid differentiation primary response 88 (MYD88). The aim of this study was to investigate the relationship of TLR1, TLR6, MYD88 and TIRAP polymorphisms with susceptibility to latent tuberculosis infection (LTBI) and tuberculosis (TB)., Methods: In total, 204 uninfected healthy controls (HC), 201 individuals with LTBI and 209 TB patients were enrolled. Two interferon-γ release assays were used to differentiate individuals with LTBI from uninfected controls. TagSNPs of the four genes were genotyped by the SNPscan TM Kit. The Haploview 4.2 and SHEsis software packages were combined to perform linkage disequilibrium (LD) and haplotype analyses. Multifactor dimensionality reduction (MDR) software was used to investigate gene-gene interaction. The Stata 12.0 software was used to perform meta-analysis of the relationship between rs5743557 and TB susceptibility., Results: The AA genotype of rs5743557 was associated with reduced TB risk (P=0.006) and the AA/GA genotypes of TLR1 rs5743604 were associated with increased TB risk (P=0.017) when the LTBI group was compared with the TB group. The frequency of TLR1 haplotype rs4833095-rs5743604 CG was significantly higher in the LTBI group than in the TB group (P=0.019877). However, only the relationship between rs5743557 and TB susceptibility remained significant after 1000-fold permutation testing (P=0.023). The meta-analysis suggested that rs5743557&#95;A was associated with decreased TB risk in the Chinese adult population (P<0.001, OR 0.80, 95% CI: 0.72-0.88). No significant gene-gene interactions were found., Conclusions: The results of our study suggest that the tagSNP rs5743557 of TLR1 is associated with the risk of TB., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Study Objectives: Untreated obstructive sleep apnea (OSA) patients have an increased risk of cardiovascular disease (CVD). Adhesion molecules, including soluble E-selectin (sE-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1), are associated with incident CVD. We hypothesized that specific genetic variants will be associated with plasma levels of adhesion molecules in suspected OSA patients. We also hypothesized that there may be an interaction between these variants and OSA., Methods: We measured levels of sE-selectin, sICAM-1 and sVCAM-1 in 491 patients with suspected OSA and genotyped them for 20 polymorphisms., Results: The most significant association was between the ABO rs579459 polymorphism and sE-selectin levels (P = 7×10-21), with the major allele T associated with higher levels. The direction of effect and proportion of the variance in sE-selectin levels accounted for by rs579459 (16%) was consistent with estimates from non-OSA cohorts. In a multivariate regression analysis, addition of rs579459 improved the model performance in predicting sE-selectin levels. Three polymorphisms were nominally associated with sICAM-1 levels but none with sVCAM-1 levels. The combination of severe OSA and two rs579459 T alleles identified a group of patients with high sE-selectin levels; however, the increase in sE-selectin levels associated with severe OSA was greater in patients without two T alleles (P = 0.05 test for interaction)., Conclusions: These genetic polymorphisms may help to identify patients at greatest risk of incident CVD and may help in developing a more precision-based approach to OSA care., Competing Interests: The authors have declared that no competing interests exist.

Toll-like receptor 1 (TLR1) participates in the innate immune response to Mycobacterium tuberculosis. This study mainly investigated the relationship between polymorphisms of TLR1 and tuberculosis (TB) susceptibility in the two Chinese populations. Totally, 1185 Han and 1216 Tibetan participants were enrolled. TagSNPs of TLR1 were selected and genotyped. Analyses of linkage disequilibrium and haplotypes were performed by software Haploview and SHEsis. Gene-gene interactions were evaluated using the nonparametric multifactor dimensionality reduction (MDR) method. Gene-by-sex interaction in the Tibetan population and gene-by-smoking interaction in the Han population were also calculated. Association between rs4833095 and TB susceptibility was evaluated by meta-analysis. In the Tibetan population, the A alleles of rs5743557 and rs5743596 were related with reduced tuberculosis risk (p < 0.001 and p = 0.001) after adjusting for confounding factors. Additionally, rs5743604&#95;A was associated with increased TB susceptibility (p = 0.004). The frequency of haplotype rs4833095-rs5743557-rs5743596-rs5743604 CAAG was significantly higher in the healthy controls (HC) group (p = 0.0009), while frequency of haplotype CGGA was higher in the TB group (p = 0.001). Significant associations were detected between rs4833095-rs5743557-rs5743604 interactions and TB susceptibility. Interactions between rs5743596 and sex in the Tibetan population, between rs5743604 and smoking in the Han population were revealed as well. However, no significant main effects were observed in the Han population. The rs4833095 was not associated with TB susceptibility after meta-analysis either. Our study suggested that SNPs of the TLR1 gene were associated with TB susceptibility in the Chinese Tibetan population, but not in the Han population., (Copyright © 2018. Published by Elsevier B.V.)

Background: Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis., Objective: We sought to investigate genetic susceptibility to PA., Methods: Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations., Results: An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10 -8 ), whereas SNPs associated with Src kinase-associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin α3 (CTNNA3), rho GTPase-activating protein 24 (ARHGAP24), angiopoietin 4 (ANGPT4), chromosome 11 open reading frame (C11orf30/EMSY), and exocyst complex component 4 (EXOC4) reached a threshold suggestive of association (P ≤ 1.49 × 10 -6 ). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10 -6 ). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10 -11 ), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 10 -6 ). Functional annotation indicated that SKAP1 regulates expression of CBX1, which colocalizes with the EMSY protein coded by C11orf30., Conclusion: This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The toll-like receptor 2 (TLR2)-mediated immune response is critical for host defense against Mycobacterium tuberculosis . There is evidence that TLR10, a TLR2 signaling modulator, may be involved in progression of tuberculosis (TB)., Methods: Using a self-validating case-control design, we tested for an association between seven TLR10 polymorphisms and susceptibility to TB in three independent series with two distinct populations. Single-nucleotide polymorphism (SNP) genotypes were determined by the SNPscan TM method. Three genetic models (additive, dominant, and recessive) as well as multiple-SNP score analyses were used to evaluate the risk of TB associated with the TLR10 SNPs., Results: By comparing TB patients with healthy controls, we observed two SNPs (rs11466617 and rs4129009) that were associated with decreased risk of TB in the Tibetan population, but did not in the Chinese Han population. Further analysis demonstrated that the rs11466617 Chengdu cohort genotype served as a protective factor against the progression of latent TB infection (LTBI) to active TB under the recessive model. None of the SNPs were significantly different in comparisons of TB-uninfected people with LTBI individuals. Additionally, when the underlying four TB-associated loci were considered together in a multiple-SNP score analysis, we observed an allele dose-dependent decrease in TB risk in Tibetans., Conclusion: Variants of TLR10 may show an ethnic specificity on susceptibility to TB in Tibetan individuals. rs11466617 affected the susceptibility to progress from LTBI to active TB disease, but was not associated with the establishment of LTBI after M. tuberculosis exposure. More studies are needed to verify this genetic epidemiological result and unravel the role of TLR10 SNPs in the pathogenesis of TB.

Objectives: Antituberculosis drug-induced hepatotoxicity (ATDH) remains a common and severe challenge in tuberculosis (TB) chemotherapy. A growing number of studies have revealed that genetic polymorphisms affect an individual's susceptibility to ATDH. The aim of this study was to explore the role of cytochrome P450 family 2 subfamily B member 6 (CYP2B6) gene polymorphisms in the development of ATDH in Chinese TB patients., Methods: CYP2B6*6 genotypes were determined in TB patients with and without ATDH. Association between polymorphisms and risk of ATDH was estimated by multiple logistic regression analysis., Results: A total of 343 eligible TB patients (166 with ATDH; 177 without ATDH) were included in this study. Analysis of all subjects revealed no statistical differences in genotype distribution between the two groups. However, the CYP2B6 *6/*6 genotype was significantly associated with decreased risk of ATDH in the male subgroup (P=0.039, OR=0.097, 95% CI: 0.011-0.885). Furthermore, in male patients, the presence of the CYP2B6*6 allele was significantly higher in the non-ATDH group compared with the ATDH group (26.2% vs. 15.5%, P=0.020, OR=0.522, 95% CI: 0.301-0.903)., Conclusions: This study is the first to demonstrate an association between CYP2B6 polymorphisms and the risk of ATDH in the Chinese population. We have shown that males who have the CYP2B6 *6/*6 genotype may be less susceptible to the development of ATDH. Further studies are required to confirm this genetic association result., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Endoplasmic reticulum (ER) stress has been recognized to play an important role in chronic inflammatory diseases such as cystic fibrosis (CF), and targeting ER stress may be useful for alleviating damaging neutrophilic inflammation in CF airways. Cellular models were used in conjunction with data from a recent CF genome-wide association study (GWAS) meta-analysis to determine modulators of ER stress-mediated inflammation. Surprisingly, cells undergoing ER stress during inflammatory stimulation showed reduced interleukin 8 (IL-8) and CXCL1 secretion (P < .001). Neutralization of CXCL1 and IL-8 reduced neutrophil chemotaxis >50% to supernatants from IL-1β-stimulated CF airway epithelial cells (P < .01). The clinical importance of these chemokines was validated by association of CXCL1 and IL8 polymorphisms with changes in lung disease severity in patients with CF (n = 6365; IL8, P = .001; CXCL1, P = .001), confirming that targeting these chemokine pathways could help improve lung disease. We determined that production of these chemokines was partially controlled by ER stress in a signal transducer and activator of transcription 3 (STAT3)-dependent manner, whereby ER stress inhibited STAT3 activation. Our findings support a role for CXCL1 and IL-8 in CF lung disease severity and identify STAT3 as a modulating pathway. Targeting these pathways may help improve health outcomes in CF., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Phagocyte Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase complex is a key enzyme that catalyzes the production of reactive oxygen species, which mediate oxygen-dependent killing of microorganisms, such as Mycobacterium tuberculosis. P22phox, encoded by CYBA, is the key regulatory subunit of NADPH oxidase. Our study aimed to investigate the association of CYBA polymorphisms with susceptibility to tuberculosis. Three SNPs (rs9932581, rs3794624 and rs4673) were genotyped in the discovery cohort composed of Chinese Han individuals. We found that the A allele of rs3794624 was a significant protective factor against tuberculosis (GA vs. GG: OR = 0.74, 95% CI 0.57-0.96; GA vs. GG+AA: OR = 0.73, 95% CI 0.56-0.95), which was then replicated in the Chinese Tibetan population (GA vs. GG: OR = 0.68, 95% CI 0.51-0.92; AA+GA vs. GG: OR = 0.70, 95% CI 0.52-0.93; GA vs. GG+AA: OR = 0.68, 95% CI 0.51-0.92). Meta-analysis including both cohorts identified overdominance as the best genetic model and provided robust evidence for the protective effect of the rs3794624 GA genotype against tuberculosis without any evidence of heterogeneity (GA vs. GG+AA: OR = 0.71, 95% CI 0.58-0.86). Our study found an association between the GA genotype of rs3794624 in CYBA with decreased tuberculosis susceptibility in two Chinese populations. Further analyses are needed to reveal the potential function of this SNP.

Objective: Antituberculosisdrug-induced hepatotoxicity (ATDH) is a common and sometimes serious side effect related to tuberculosis (TB) treatment. A number of risk factors and host genetics contribute to the development of ATDH. However, genetic factors of ATDH remain to be identified. Silent Information Regulator 1 (SIRT1), an essential metabolism gene, was proved to be involved in ATDH in mice. The aim of this investigation was to study the association between ATDH and tag-single nucleotide polymorphisms (tag-SNPs) of the SIRT1 gene in a prospective cohort study in patients with TB., Methods: 280 newly diagnosed TB patients were recruited in this study before starting first line anti-TB treatment and were followed up for 3 months after initiating anti-TB therapy. The tag-SNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese Beijing. Genotyping was performed by polymerase chain reaction (PCR) and the Sequenom MassARRAY iPLEX platform., Results: 24 (9.8%) of the 245 patients included in the final analysis developed hepatotoxicity during the following up period. No significant differences in the allele, genotype, or haplotype frequency distributions of the tag- SNPs (rs7069102, rs2273773, rs4746720) of the SIRT1 gene were identified between the ATDH and non-ATDH groups (all p > 0.05)., Conclusions: The SIRT1 gene may not contribute to the risk for developing hepatotoxicity during anti-TB treatment in the Han Chinese population.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a pauci-immune necrotizing vasculitis that involves small vessels. Herein, we report an extremely rare case of rifampicin (RFP)-induced AAV. A 42-yearold female was transferred to the West China Hospital due to cough with phlegm for 3 months, fever for 1 month, and fatigue for 2 weeks. The patient was diagnosed with pulmonary tuberculosis (TB) and received anti-TB treatment with isoniazid, RFP, ethambutol, and pyrazinamide (PZA) at her local hospital. After 5 days of anti-TB treatment, her creatinine level rose to 420.2 μmol/L from a normal level prior to anti-TB treatment. Serum proteinase 3 (PR3)-ANCA was positive. After discontinuing the anti-TB drugs and administering protective renal treatment, her renal function improved, whereas PR3-ANCA remained positive. With RFP rechallenge after transfer to our hospital, the patient developed oliguria. Her urine volume increased gradually after RFP was discontinued 3 days later. Therefore, RFPinduced AAV was suspected. Eventually, the patient received prednisone and anti-TB therapy, including isoniazid, ethambutol, PZA, and moxifloxacin. After 2 months, PZA was discontinued. During 6 months of normal, and PR3-ANCA became negative at 4 months. This outcome is characteristic of RFP-induced AAV.

Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse reaction to anti-tuberculosis (TB) treatment. Thioredoxin reductase 1 (TXNRD1), encoded by the TXNRD1 gene, is an important enzyme involved in oxidant challenge. TXNRD1 plays a key role in regulating cell growth and transformation, and protects cells against oxidative damage. We investigated the association between TXNRD1 polymorphisms and ATDH susceptibility. In this prospective study, 280 newly diagnosed TB patients were followed-up for 3 months after beginning anti-TB therapy. Tag single-nucleotide polymorphisms (tag-SNPs) of TXNRD1 were selected using Haploview 4.2 based on the HapMap database of the Chinese Han in Beijing (CHB) panel. Genotyping was performed using the MassARRAY platform. Of the 280 patients enrolled in this study, 33 were lost to follow-up, 24 had ATDH, and 223 were free from ATDH. After adjusting for sex, age, smoking status, and body mass index, there were no significant differences in the allele and genotype frequency distributions of TXNRD1 SNPs between the ATDH and non-ATDH groups (all P > 0.05). The haplotype analysis showed that haplotype TCAGCC was associated with an increased risk of ATDH susceptibility [P = 0.024, OR (95%CI) = 6.273 (1.023-38.485)]. Further stratified analyses showed that the haplotype TCAGCC was associated with ATDH susceptibility in female subjects [P = 0.036, OR (95%CI) = 5.711 (0.917-35.560)] and non-smokers [P = 0.029, OR (95%CI) = 6.008 (0.971-37.158)]. Our results suggest that TXNRD1 variants may favor ATDH susceptibility in females and non-smokers. Further studies are required to verify this association., Competing Interests: The authors declare no conflict of interest.

Background: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most common adverse effects associated with tuberculosis (TB) therapy. Animal studies have demonstrated important roles of glutathione S-transferases in the prevention of chemical-induced hepatotoxicity. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of glutathione S-transferase P1 (GSTP1) and ATDH in TB patients., Methods: We used two independent samples for this genetic association study. In the initial prospective study, 322 newly diagnosed TB patients were followed up for three months after initiating anti-TB therapy. In an independent retrospective study, 115 ATDH patients and 116 patients without ATDH were selected to verify the results of the prospective study. Tag-SNPs of GSTP1 were genotyped either with the MassARRAY platform or the improved multiple ligase detection reaction (iMLDR) method. The associations between SNPs and ATDH were analyzed by logistic regression analysis adjusting for confounding factors., Results: Of the 322 patients recruited in the prospective cohort, 35 were excluded during the 3 months of follow-up, and 30 were diagnosed with ATDH and were considered as the ATDH group. The remaining 257 subjects without ATDH were considered as the non-ATDH group. After correction for potential confounding factors, significant differences were found for rs1695 (A>G) under an allelic model (OR = 3.876, 95%CI: 1.258011.905; P = 0.018). In the retrospective study, rs1695 allele A also had a higher risk of ATDH (OR = 2.10, 95%CI: 1.17-3.76; P = 0.012). We only found rs4147581AA genotype under a dominant model was related to ATDH in the prospective study (OR = 2.578, 95%CI: 1.076-6.173; P = 0.034)., Conclusions: This is the first study to suggest that GSTP1 genotyping can be an important tool for identifying patients who are susceptible to ATDH. This result should be verified in independent large sample studies and also in other ethnic populations.

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., (© 2016 John Wiley & Sons Ltd.)

BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are putative innate immune molecules expressed in the upper airways. Because of their hypothesized roles in airway defense, these molecules may contribute to lung disease severity in cystic fibrosis (CF). We interrogated BPIFA1/BPIFB1 single-nucleotide polymorphisms in data from an association study of CF modifier genes and found an association of the G allele of rs1078761 with increased lung disease severity (P = 2.71 × 10(-4)). We hypothesized that the G allele of rs1078761 is associated with decreased expression of BPIFA1 and/or BPIFB1. Genome-wide lung gene expression and genotyping data from 1,111 individuals with lung disease, including 51 patients with CF, were tested for associations between genotype and BPIFA1 and BPIFB1 gene expression levels. Findings were validated by quantitative PCR in a subset of 77 individuals. Western blotting was used to measure BPIFA1 and BPIFB1 protein levels in 93 lung and 101 saliva samples. The G allele of rs1078761 was significantly associated with decreased mRNA levels of BPIFA1 (P = 4.08 × 10(-15)) and BPIFB1 (P = 0.0314). These findings were confirmed with quantitative PCR and Western blotting. We conclude that the G allele of rs1078761 may be detrimental to lung function in CF owing to decreased levels of BPIFA1 and BPIFB1.

Objective: We reported association of haplotypes formed by IL-1b (IL1B)-511C/T (rs16944) and a variable number of tandem repeats (rs2234663) in intron 3 of IL-1 receptor antagonist (IL1RN) with rate of lung function decline in smoking-induced COPD. The aim of current study was to further investigate this association., Methods: We genotyped an additional 19 polymorphisms in IL1 cluster (including IL1A, IL1B and IL1RN) in non-Hispanic whites who had the fastest (n = 268) and the slowest (n = 292) decline of FEV1% predicted in the same study. We also analyzed the association of all 21 polymorphisms with serum CRP levels., Results: None of 21 polymorphisms showed significant association with rate of decline of lung function or CRP levels after adjusting for multiple comparisons. Before adjusting for multiple comparisons, only IL1RN&#95;19327 (rs315949) showed significant association with lung function decline (P = 0.03, additive model). The frequencies of genotypes containing the IL1RN&#95;19327A allele were 71.9% and 62.2%, respectively in the fast and slow decline groups (P = 0.02, odds ratio = 1.6, 95% confidence interval = 1.1-2.3); the IL1B&#95;5200 (rs1143633) and rs2234663 in IL1RN were associated with serum CRP levels (P=0.04 and 0.03, respectively)., Conclusions: No single marker was significantly associated with either rate of lung function decline or serum CRP levels.

Background: Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48,201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs., Methods: The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature., Findings: SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD., Interpretation: The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico., Funding: The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS., Competing Interests: Declaration of interests DCN is an employee of Merck and Co. DSP reports grants to the university and consultancy fees to the university from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Takeda, and TEVA outside of the submitted work. DDS reports personal fees from Amgen, grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, grants from Novartis, outside of the submitted work. DJ reports grants from the European Union. IPH reports grants from MRC during the conduct of the study. JK reports grants from the Academy of Finland and from the European Union during the conduct of the study, and personal fees from Pfizer, outside of the submitted work. JBW is an employee of Pfizer. PAC reports grants from National Institutes of Health during the conduct of the study. ML has received payments from Boston Scientific, AstraZeneca, and Merck for lectures and from GSK for a consultants’ meeting. WTi reports personal fees from Pfizer, GSK, Chiesi, and Roche Diagnostics/Ventana, and grants from Dutch Asthma Fund, outside of the submitted work. WTa reports personal fees from Boehringer Ingelheim Pharmaceuticals, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Recent candidate gene and genome-wide association studies have identified "protective" associations between the single-nucleotide polymorphism (SNP) rs1837253 in the TSLP gene and risk for allergy, asthma, and airway hyperresponsiveness. The absence of linkage disequilibrium of rs1837253 with other SNPs in the region suggests it is likely a causal polymorphism for these associations, having functional consequences. We hypothesized that rs1837253 genotype would influence TSLP secretion from mucosal surfaces. We therefore evaluated the secretion of TSLP protein from primary nasal epithelial cells (NECs) of atopic and nonatopic individuals and its association with rs1837253 genotype. We found that although atopic sensitization does not affect the secretion of TSLP from NECs, there was decreased TSLP secretion in NECs obtained from heterozygous (CT; 1.8-fold) and homozygous minor allele (TT; 2.5-fold) individuals, as compared with NECs from homozygous major allele individuals (CC; P<0.05), after double-stranded RNA (dsRNA) stimulation (50 μg ml(-1)). Our novel results show that rs1837253 polymorphism may be directly involved in the regulation of TSLP secretion. This may help explain the protective association of this genetic variant with asthma and related traits. Identifying functional consequences of SNPs in genes with previously reported clinical associations is critical in understanding and targeting allergic inflammation.

Background: Cumulative studies have shown that asthma is associated with depression but the underlying mechanisms are poorly understood. This study aimed to determine whether asthma with depression is characterized by unique pathophysiological pathways by analyzing the global gene expression patterns of CD4(+) T-cells from asthmatics with or without depression., Materials and Methods: Four groups of subjects (non-depressive asthmatics, depressive asthmatics, depression patients, and healthy controls) consisting of 6 participants in each group were studied. Peripheral CD4(+) T-cells were isolated and the global transcriptomic profiles were defined by using the Agilent SurePrint G3 Human GE 8x60K microarray. The differences in transcriptomic profiles between asthma with or without depression, depression patients and healthy controls were examined. Pathway enrichment analyses of differentially expressed genes were performed using the Ingenuity Pathway Analysis. Selected genes were verified and correlated to the clinical characteristics., Results: A total of 1448 differentially expressed transcripts were identified in any of the non-depressive asthma vs. healthy control, depressive asthma vs. healthy control, or depression vs. healthy control comparisons after correction for multiple comparisons. Among these, 156 were demonstrated as differentially expressed genes only in depressive asthma vs. healthy control. Twenty significant biological pathways were identified and were involved in inflammation, metabolism, immunity, tumor and cell cycle. Increased expression of phosphoinositide-3-kinase, regulatory subunit 1 (alpha) was confirmed in depressive asthmatics and it was inversely correlated with lung function (FEV1/FVC%)., Conclusions: Asthmatics with depression exhibit unique pathophysiological pathways and this result may provide clues for specific molecular mechanisms underlying asthma with depression., (Copyright © 2015. Published by Elsevier B.V.)

Objective: Reactive oxygen species (ROS) play a major role in the nonspecific innate immune response to invading microorganisms, such as Mycobacterium tuberculosis (MTB). Gp91phox, encoded by CYBB, serves as a key functional subunit of the Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase complex, which is pivotal to ROS generation. Therefore, the aim of the study was to investigate the association of CYBB polymorphisms with tuberculosis (TB) susceptibility., Methods: In total, 636 TB patients and 608 healthy, age and gender matched controls were enrolled in this study. All subjects were unrelated ethnic Han Chinese. Two tagSNPs were selected from the HapMap database and genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry., Results: After adjusting for confounders including age, gender and smoking, rs5917471 allele T showed significant association with decreased risk of TB (OR 0.745, 95% CI 0.556-0.999) and pulmonary TB (OR 0.618, 95% CI 0.410-0.931). However, no difference in allelic distribution was observed for the rs6610650 G/A polymorphism with respect to TB or different clinical types of TB. Further stratified analyses demonstrated the protective effect of allele T of rs5917471 was stronger among males (OR 0.500, 95% CI 0.295-0.846), smokers (OR 0.462, 95% CI 0.239-0.896), and male smokers (OR 0.372, 95% CI 0.182-0.761); the individuals carrying the A allele of rs6610650 exhibited an decreased risk of TB among males, smokers and male smokers, with OR (95% CI) of 0.535 (0.290-0.984), 0.442 (0.198-0.988), and 0.350 (0.145-0.845), respectively. There were no statistically significant differences in haplotype distribution between TB and control groups. Smoking and rs5917471 formed the best gene-environment interaction model with the testing balanced accuracy of 53.29% and cross-validation consistency of 9/10., Conclusions: This is the first study of the association of CYBB polymorphisms with TB. Our findings suggest that the CYBB polymorphisms are significantly correlated with reduced risk of TB, especially among male smokers. Further studies are needed to verify this association., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Oxidative stress is involved in the pathogenesis of airway obstruction in α1-antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in α1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 α1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from blood and DNA from lung tissue in a subset of 51 controls. We found that telomere length in the blood was significantly longer in α1-antitrypsin deficient COPD patients compared with control COPD patients (p = 1×10(-29)). Telomere length was not related to lung function in α1-antitrypsin deficient patients (p = 0.3122) or in COPD controls (p = 0.1430). Although mean telomere length was significantly shorter in the blood when compared with the lungs (p = 0.0078), telomere length was correlated between the two tissue types (p = 0.0122). Our results indicate that telomere length is better preserved in α1-antitrypsin deficient COPD patients than in non-deficient patients. In addition, measurement of telomere length in the blood may be a suitable surrogate for measurement in the lung.