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Jamrozik E.,University of Western Australia | Jamrozik E.,Busselton Population Medical Research Foundation | Musk A.W.,University of Western Australia | Musk A.W.,Busselton Population Medical Research Foundation
Respirology | Year: 2011

The Asia-Pacific region is home to a large heterogeneous population whose respiratory health is influenced by diverse social, economic and environmental factors. Despite this variability, the most prevalent causes of respiratory morbidity and mortality are tobacco smoking, infection, and air pollution. This review aims to summarize current respiratory health issues in the region including smoking-related diseases especially COPD, lung cancer and infectious problems such as pandemic influenza, the severe acute respiratory syndrome coronavirus, bacterial pneumonia and tuberculosis, aswell as the contribution of air pollution to respiratory disease. Published data on trends in the epidemiology and management of respiratory diseases and are summarized; finally, the limitations of available data and projections for the future of respiratory health in the region are discussed. © 2010 Commonwealth of Australia Respirology © 2010 Asian Pacific Society of Respirology. Source

Artigas M.S.,University of Leicester | Wain L.V.,University of Leicester | Repapi E.,University of Leicester | Repapi E.,University of Oxford | And 56 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2011

Rationale: Genomic loci are associated with FEV 1 or the ratio of FEV 1to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects),we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV 1 (b = -72.21 ml, P = 3.90 ×10 -4) and FEV 1/FVC (β = -1.53%, P=6.35×10 -6), and with COPD (odds ratio=1.63, P=1.46×10 -5). Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score. Source

Thun G.A.,Swiss Tropical and Public Health Institute | Thun G.A.,University of Basel | Imboden M.,Swiss Tropical and Public Health Institute | Imboden M.,University of Basel | And 49 more authors.
PLoS Genetics | Year: 2013

Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = -0.068 g/L per minor allele (P = 1.20*10-12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population. © 2013 Thun et al. Source

James A.L.,Busselton Population Medical Research Foundation | James A.L.,University of Western Australia | Knuiman M.W.,University of Western Australia | Divitini M.L.,University of Western Australia | And 8 more authors.
European Respiratory Journal | Year: 2010

Asthma prevalence has increased worldwide; although less so in developed countries recently. This study assessed changes in the prevalence of asthma and related symptoms in the Busselton community since 1966. Cross-sectional respiratory health surveys of Busselton adults were conducted in 1966, 1969, 1972, 1975, 1981, 1990 and 2005-2007. Logistic regression models were used to estimate prevalence rates of asthma, respiratory symptoms, smoking, airway hyperresponsiveness (AHR) and atopy and to make comparisons in 2005-2007 and previous survey years. Asthma was defined as ever having doctor-diagnosed asthma (DDA). The prevalence of DDA was around 6% from 1966 to 1975, 8% in 1981 and rose to 19% in 2005-2007. From 1981 to 2005-2007, smoking prevalence declined and obesity and atopy increased but changes in these variables explained only a small part of the increase in DDA. Wheeze and cough/phlegm increased but AHR, breathlessness and doctor-diagnosed bronchitis remained relatively stable over the same period. These observations indicate that the increase in DDA is partly explained by increased symptoms and atopy. The lack of changes in AHR and doctor-diagnosed bronchitis suggests that factors such as diagnostic transfer and increased awareness of asthma have also contributed to the rise in prevalence of DDA. Copyright©ERS Journals Ltd 2010. Source

Musk A.W.,Busselton Population Medical Research Foundation | Musk A.W.,University of Western Australia | Knuiman M.,Busselton Population Medical Research Foundation | Knuiman M.,University of Western Australia | And 10 more authors.
European Respiratory Journal | Year: 2011

The aim of this study was to examine how objective measures related to lung function cluster in the general population and how the patterns relate to asthma and bronchitis as diagnosed by a doctor (DDA and DDB, respectively). A cross-sectional survey of an age-stratified random general population sample of 1,969 adults from the electoral register of Busselton (Australia) was performed in 2005-2007. Respiratory symptoms, DDA ever, DDB ever, recent wheezing and smoking history, together with anthropometric measurements, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), methacholine challenge or bronchodilator response, exhaled nitric oxide (eNO), skin-prick tests to common allergens, and blood eosinophil and neutrophil counts were studied. Cluster analysis (variables sex, age, atopy, FEV1% predicted, FEV1/FVC, airway hyperresponsiveness, eNO, log eosinphil count, log neutrophil count and body mass index) was used to identify phenotypic patterns. Seven clusters (subjects with DDA and DDB, respectively) were identified: normal males (n=467; 7 and 13%), normal females (n=477; 12 and 18%), obese females (n=250; 16 and 28%), atopic younger adults (n=330; 21 and 17%), atopic adults with high eNO (n=130; 30 and 25%), atopic males with reduced FEV1 (n=103; 33 and 32%) and atopic adults with bronchial hyperreactivity (n=212; 40 and 26%). The clinical diagnosis of asthma (ever) and bronchitis (ever) is not specific for any of the clustering patterns of airway abnormality. Copyright©ERS 2011. Source

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