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author:("gulik, amend")
1.  Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease 
Respiratory Research  2014;15(1):113.
Chronic bronchitis (CB) is one of the classic phenotypes of COPD. The aims of our study were to investigate genetic variants associated with COPD subjects with CB relative to smokers with normal spirometry, and to assess for genetic differences between subjects with CB and without CB within the COPD population.
We analyzed data from current and former smokers from three cohorts: the COPDGene Study; GenKOLS (Bergen, Norway); and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). CB was defined as having a cough productive of phlegm on most days for at least 3 consecutive months per year for at least 2 consecutive years. CB COPD cases were defined as having both CB and at least moderate COPD based on spirometry. Our primary analysis used smokers with normal spirometry as controls; secondary analysis was performed using COPD subjects without CB as controls. Genotyping was performed on Illumina platforms; results were summarized using fixed-effect meta-analysis.
For CB COPD relative to smoking controls, we identified a new genome-wide significant locus on chromosome 11p15.5 (rs34391416, OR = 1.93, P = 4.99 × 10-8) as well as significant associations of known COPD SNPs within FAM13A. In addition, a GWAS of CB relative to those without CB within COPD subjects showed suggestive evidence for association on 1q23.3 (rs114931935, OR = 1.88, P = 4.99 × 10-7).
We found genome-wide significant associations with CB COPD on 4q22.1 (FAM13A) and 11p15.5 (EFCAB4A, CHID1 and AP2A2), and a locus associated with CB within COPD subjects on 1q23.3 (RPL31P11 and ATF6). This study provides further evidence that genetic variants may contribute to phenotypic heterogeneity of COPD.
Trial registration NCT00608764, NCT00292552
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0113-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4190389  PMID: 25241909
Pulmonary disease; Chronic obstructive; Chronic bronchitis; Genome-wide association study
2.  Feasible and simple exclusion criteria for pulmonary reference populations 
Thorax  2007;62(9):792-798.
International guidelines recommend that pulmonary reference populations consist of never‐smokers without respiratory diseases or symptoms, but the diseases and symptoms are not clearly specified. The present study aimed to identify simple exclusion criteria for defining pulmonary reference populations.
Based on a random sample from a general population (the parent population), 2358 subjects aged 26–82 years performed spirometric tests. From this sample, subjects were stepwise excluded according to self‐reported obstructive lung diseases, symptoms and smoking history. Four increasingly more healthy respiratory reference populations were formed. Prediction equations for the median and lower limit of normal lung function were derived using quantile regression analysis.
Subjects without self‐reported obstructive lung diseases or the cardinal respiratory symptoms of breathlessness, cough or wheeze (population B), never‐smokers without cardinal symptoms (population C) and never‐smokers without any respiratory symptoms (population D) constituted 50% (n = 1184), 23% (n = 539) and 14% (n = 331) of the parent population (population A), respectively. The largest discrepancy between prediction equations was found between the parent population and the population without cardinal respiratory symptoms (population B) (p<0.05). Minor changes in the reference equations were also seen when excluding ever‐smokers (population C). There was no additional change with exclusion of other respiratory symptoms (population D). Age‐related decline in lung function was steepest in the parent population.
Obstructive lung diseases, smoking history, breathlessness, cough and wheeze are optimal exclusion criteria for a pulmonary reference population. Further validation of the exclusion criteria identified in this study is recommended with identical wording in other and larger multinational populations.
PMCID: PMC2117321  PMID: 17389756

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