Chao-Chien Wu

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

BackgroundTo investigate whether the toll-like receptor 2 polymorphisms could influence susceptibility to pulmonary TB, its phenotypes, and blood lymphocyte subsets.MethodsA 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.ResultsWe 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/μl, 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/μl, 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/μl, p = 0.004).ConclusionsTLR2 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.

Differences in clinical and laboratory characteristics and disease severity between children and adults with dengue virus infection in Taiwan, 2002.

To compare the clinical and laboratory characteristics and disease severity between adults and children with dengue in Taiwan in 2002, we retrospectively studied 661 serologically confirmed dengue-infected patients (606 adults and 55 children) admitted between June and December 2002 to a single medical centre. The medical charts of the patients were reviewed for demographic, clinical, laboratory and imaging information. Compared with children, adult patients were found to have: higher incidences of arthralgia (P<0.001), myalgia (P=0.002), headache (P=0.028), abdominal pain (P=0.004) and upper gastrointestinal bleeding (P=0.013); lower platelet counts (P<0.001), prothrombin time (P=0.030) and serum albumin levels (P=0.037); a higher incidence of elevated alanine aminotransferase levels (P=0.001); and a higher prevalence of dengue haemorrhagic fever (DHF) (14.4% vs. 3.6%; P=0.026). The current data showed differences in clinical manifestations and laboratory characteristics between children and adults with dengue virus infection. Notably, a higher incidence of DHF was observed in adult patients compared with children in the 2002 dengue epidemic in Taiwan.

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.

Prognostic values of serum IP-10 and IL-17 in Patients with Pulmonary Tuberculosis

Objective: To identify patients at high risk of relapse after anti-tuberculosis (TB) therapy or with poor long-term outcomes. Methods: Fifty-one patients with pulmonary TB: 7 were classified as high association with both cavitations on initial chest radiography and positive sputum smear/cultures after two months of anti-TB treatment (HA group); 19 medium association (MA, one risk alone); and 25 low association (LA, neither risk). Serum interferon (IFN)-γ-inducible protein 10 (IP-10), interleukin-17 (IL-17), and C-reactive protein levels were investigated. Results: There was a trend towards higher serum IP-10 levels (p = 0.042) for HA patients throughout the 6-month treatment period. Month-2 IP-10 levels were higher in the HA than in the MA/LA group (656.2 ± 234.4 vs. 307.6 ± 258.5 pg/ml, adjusted p = 0.005). Receiver operating characteristic curves showed that the risk of relapse was well-captured by month-2 IP-10 levels at a cut-off value of 431 pg/ml (AUC=0.857, 95% CI 0.75–0.97, p = 0.003). Month-2 serum IL-17 levels were lower in non-survivors than survivors (15.7 ± 2.9 pg/ml vs. 24.6 ± 8.2 pg/ml, p = 0.001). Multivariate analysis demonstrated that a month-2 serum IL-17 level of ≤ 17 pg/ml (p = 0.026) was independently associated with all-cause mortality. Conclusions: Serum IP-10 and IL-17 levels after 2 months of anti-TB treatment may be biomarkers for estimating risk of both cavitation and delayed sputum conversion, and for predicting long-term mortality, respectively.

A new grid-scale model simulating the spatiotemporal distribution of PM2.5-PAHs for exposure assessment.

Exposure to polycyclic aromatic hydrocarbons (PAHs) associated with ambient air particulate matter (PM) poses significant health concerns. Several modeling approaches have been developed for simulating ambient PAHs, but no hourly intra-urban spatial data are currently available. The aim of this study is to develop a new modeling strategy in simulating, on an hourly basis, grid-scale PM2.5-PAH levels. PM and PAHs were collected over a one-year time frame through an established air quality monitoring network within a metropolitan area of Taiwan. Multivariate linear regression models, in combination with correlation analysis and PAH source identification by principal component analysis (PCA), were performed to simulate hourly grid-scale PM2.5-PAH concentrations, taking criteria pollutants and meteorological variables selected as possible predictors. The simulated levels of 72-h personal exposure were found to be significantly (R=0.729**, p<0.01) correlated with those analyzed from portable personal monitors. A geographic information system (GIS) was used to visualize spatially distributed PM2.5-PAH concentrations of the modeling results. This new grid-scale modeling strategy, incorporating the output of simulated data by GIS, provides a useful and versatile tool in personal exposure analysis and in the health risk assessment of air pollution.

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.

CHI3L1 polymorphisms associate with asthma in a Taiwanese population

BackgroundA genome-wide association study uncovered Chitinase 3 like 1 (CHI3L1) as a candidate gene for asthma susceptibility. CHI3L1, which encodes the YKL-40 protein, is associated with asthma in Western European and American populations and with atopy in a Korean population. However, asthma-associated polymorphisms remain unknown for a Taiwanese population.MethodsWe enrolled 628 adult asthmatic patients and 1:1 age-sex matched community-based controls in southern Taiwan and performed a combined effect sizes analysis to test if CHI3L1 polymorphisms were related to genetic risks for asthma in the Asian population. Ten tagSNP polymorphisms for the CHI3L1 gene were selected from the HapMap database and genotyped using a TaqMan allelic discrimination assay.ResultsAdjusted odds ratios of the CHI3L1 rs1538372 CC genotype (aOR = 1.97, 95% CI: 1.23–3.14) and the rs10399931 GG genotype (aOR = 1.77, 95% CI: 1.13–2.77) were significantly associated with asthma in the Taiwanese populations. Predictive values of forced expiratory volume in the first second of the forced vital capacity (12.37%, P = 0.03) and of forced vital capacity (12.10%, P = 0.036) decreased in conjunction with an increase in YKL-40 levels among CHI3L1 rs1538372 CC carriers; these values were 16.1% (P = 0.004) and 14.5% (P = 0.011), respectively, among CHI3L1 rs10399931 GG carriers. Furthermore, steroid use by asthma patients did not affect serum YKL-40 levels, but both polymorphisms had significant effects on YKL-40 levels in asthma patients who used steroids.ConclusionsOur findings suggest that the CHI3L1 polymorphisms rs1538372 and rs10399931 can be used as genetic markers for predicting asthma risk in the Taiwanese population.

Aberrant Toll-like receptor 2 promoter methylation in blood cells from patients with pulmonary tuberculosis

OBJECTIVES Toll-like receptor 2 (TLR2) is a major mediator of innate immunity against tuberculosis (TB). This study aimed to determine if TLR2 promoter DNA methylation is associated with pulmonary TB. METHODS The DNA methylation levels of 20 CpG sites over the TLR2 promoter region and TLR2 gene/protein expressions of immune cells of the blood were examined in 99 sputum culture-positive pulmonary TB patients and 77 healthy subjects (HS). RESULTS TB patients had higher methylation levels over five CpG sites (3, 7, 9, 13, and 18), lower TLR2 gene expression, lower TLR2 expression on monocyte, higher TLR2 expression on NK cell, and higher serum TNF-α/IFN-γ levels than HS after adjusting for confounding factors. Patients with a high bacillary load had lower methylation levels at CpG-15, -17, and -20. Patients with drug-resistant TB had higher CpG-18 methylation levels and lower TLR2 expression on NK cell. Patients with far advanced lesion on chest radiograph had higher serum TNF-α level and higher TLR2 expression on NK cell. Patients with a high TLR2 expression on NK cell had lower one-year survival. CpG-18 methylation level, TLR2 expressions on monocyte/NK cell, and TNF-α/IFN-γ levels were all reversed to normal after 6-month anti-TB treatment. CONCLUSIONS Aberrant methylation of certain CpG sites over TLR2 promoter region is associated with active pulmonary TB or its phenotypes, probably through the down-regulation of TLR2 expression.

The Polymorphisms of C‐Reactive Protein Gene Modify the Association Between Central Obesity and Lung Function in Taiwan Asthmatics

High‐sensitivity C‐reactive protein (hs‐CRP) concentrations and obesity are proposed to have a significant relationship with impairment of lung function, but little has been reported to date on the association between CRP gene and lung function. We studied the association of three tagSNPs (tag single nucleotide polymorphisms) of CRP gene and their interactions with central obesity on lung function. A total of 384 asthmatic adults and 384 controls who were 1:1 matched by sex and age were recruited for this study. Three tagSNPs polymorphisms for CRP rs1417938, rs1800947 and rs1205 were selected from HapMap data and genotyping by using TaqMan allelic discrimination assay. A questionnaire interview, body composition and pulmonary function tests were performed. CRP single nucleotide polymorphisms (SNPs) did not increase the risk of asthma, but CRP rs1205 CC genotype significantly decreased the predictive value of forced vital capacity (FVC) in the asthma group (adjusted mean change = −7.54%, 95% CI = −13.82 to −1.25%). Waist‐to‐hip ratio, not body mass index, also decreased the predictive value of FVC in asthmatics. The subjects with central obesity who carried CRP SNPs have a significant reduction effect in lung function. The current results suggest that central obesity may play a major role in lung function, and these effects were modified significantly by the polymorphisms for CRP gene.

Role of gender disparity of circulating high-sensitivity C-reactive protein concentrations and obesity on asthma in Taiwan

Background Several studies have suggested that the association between obesity and asthma may be stronger in females than in males, but the reason is still unclear.