Genome-wide association study of lung function and clinical implication in heavy smokers.
ABSTRACT: BACKGROUND:The aim of this study is to identify genetic loci associated with post-bronchodilator FEV1/FVC and FEV1, and develop a multi-gene predictive model for lung function in COPD. METHODS:Genome-wide association study (GWAS) of post-bronchodilator FEV1/FVC and FEV1 was performed in 1645 non-Hispanic White European descent smokers. RESULTS:A functional rare variant in SERPINA1 (rs28929474: Glu342Lys) was significantly associated with post-bronchodilator FEV1/FVC (p = 1.2 × 10- 8) and FEV1 (p = 2.1 × 10- 9). In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 × 10- 4) and severity (OR = 4.1; p = 0.0036). Heterozygous subjects (CT genotype) had significantly lower lung function and higher percentage of COPD and more severe COPD than subjects with the CC genotype. 8.6% of the variance of post-bronchodilator FEV1/FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking (P < 2.2 × 10- 16). CONCLUSIONS:This study is the first to show genome-wide significant association of rs28929474 in SERPINA1 with lung function. Of clinical importance, heterozygotes of rs28929474 (4.7% of subjects) have significantly reduced pulmonary function, demonstrating a major impact in smokers. The multi-gene model is significantly associated with CT-based emphysema and clinical outcome measures of severity. Combining genetic information with demographic and environmental factors will further increase the predictive power for assessing reduced lung function and COPD severity.
Project description:BACKGROUND:Several recessive Mendelian disorders are common in Europeans, including cystic fibrosis (CFTR), medium-chain-acyl-Co-A-dehydrogenase deficiency (ACADM), phenylketonuria (PAH) and alpha 1-antitrypsin deficiency (SERPINA1). METHODS:In a multicohort study of >19,000 older individuals, we investigated the relevant phenotypes in heterozygotes for these genes: lung function (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC)) for CFTR and SERPINA1; cognitive measures for ACADM and PAH; and physical capability for ACADM, PAH and SERPINA1. RESULTS:Findings were mostly negative but lung function in SERPINA1 (protease inhibitor (PI) Z allele, rs28929474) showed enhanced FEV1 and FVC (0.13 z-score increase in FEV1 (p=1.7 × 10(-5)) and 0.16 z-score increase in FVC (p=5.2 × 10(-8))) in PI-MZ individuals. Height adjustment (a known, strong correlate of FEV1 and FVC) revealed strong positive height associations of the Z allele (1.50 cm increase in height (p=3.6 × 10(-10))). CONCLUSIONS:The PI-MZ rare (2%) SNP effect is nearly four times greater than the 'top' common height SNP in HMGA2. However, height only partially attenuates the SERPINA1-FEV1 or FVC association (around 50%) and vice versa. Height SNP variants have recently been shown to be positively selected collectively in North versus South Europeans, while the Z allele high frequency is localised to North Europe. Although PI-ZZ is clinically disadvantageous to lung function, PI-MZ increases both height and respiratory function; potentially a balanced polymorphism. Partial blockade of PI could conceivably form part of a future poly-therapeutic approach in very short children. The notion that elastase inhibition should benefit patients with chronic obstructive pulmonary disease may also merit re-evaluation. PI is already a therapeutic target: our findings invite a reconsideration of the optimum level in respiratory care and novel pathway potential for development of agents for the management of growth disorders.
Project description:Asthma-COPD overlap syndrome (ACOS) prevalence varies depending on the studied population and definition criteria. The prevalence and clinical characteristics of ACOS in an at-risk COPD primary care population from Latin America was assessed.Patients ?40 years, current/ex-smokers and/or exposed to biomass, attending routine primary care visits completed a questionnaire and performed spirometry. COPD was defined as post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC)?<?0.70; asthma was defined as either prior asthma diagnosis or wheezing in the last 12 months plus reversibility (increase in post-bronchodilator FEV1 or FVC ?200 mL and ?12%); ACOS was defined using a combination of COPD with the two asthma definitions. Exacerbations in the past year among the subgroups were evaluated.One thousand seven hundred forty three individuals completed the questionnaire, 1540 performed acceptable spirometry, 309 had COPD, 231 had prior asthma diagnosis, and 78 asthma by wheezing?+?reversibility. ACOS prevalence in the total population (by post-bronchodilator FEV1/FVC?<?0.70 plus asthma diagnosis) was 5.3 and 2.3% by post-bronchodilator FEV1/FVC?<?0.70 plus wheezing?+?reversibility. In the obstructive population (asthma or COPD), prevalence rises to 17.9 and 9.9% by each definition, and to 26.5 and 11.3% in the COPD population. ACOS patients defined by post-bronchodilator FEV1/FVC?<?0.7 plus wheezing?+?reversibility had the lowest lung function measurements. Exacerbations for ACOS showed a prevalence ratio of 2.68 and 2.20 (crude and adjusted, p?<?0.05, respectively) (reference COPD).ACOS prevalence in primary care varied according to definition used. ACOS by post-bronchodilator FEV1/FVC?<?0.7 plus wheezing?+?reversibility represents a clinical phenotype with more frequent exacerbations, which is probably associated with a different management approach.
Project description:While the slope of decline in FEV1 has traditionally been calculated from the post- rather than the pre-bronchodilator measurement in COPD interventional trials, it is not clear whether and to what extent these two slopes differ in symptomatic patients with COPD. Therefore, we used data from the 4-year UPLIFT trial of tiotropium 18 mcg QD vs. placebo to compare annual rates of change in pre- vs. post-bronchodilator FEV1 in 5041 patients with moderate to very severe COPD (mean FEV1 48% pred) in whom the post-bronchodilator FEV1 was measured after 4 inhalations of two different classes of short-acting inhaled bronchodilators at baseline and 1 month and every 6 months post-randomization over 4 years. Linear mixed effects models were used to estimate annual rates of decline in FEV1 and FVC pre- and post-bronchodilator in each treatment group separately, after adjusting for height, gender, smoking status, baseline % predicted FEV1 or FVC, and baseline acute % improvement in lung function. The slopes of the post-bronchodilator FEV1 and FVC were significantly steeper than the pre-bronchodilator slopes regardless of treatment arm (p < 0.001), while the estimated variances of the slopes were similar. Post-bronchodilator increases in FEV1 and FVC diminished progressively and significantly (p < 0.0001) over the 4-year trial, suggesting a possible explanation for the significant differences between the pre- and post-bronchodilator slopes. While the reasons for these differences are not completely clear, they are important to consider when assessing treatment effects on rates of decline in FEV1 and FVC.
Project description:Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n?=?13,532).Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value?=?2.17?×?10(-11)), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value?=?5.94?×?10(-10)); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value?=?8.99?×?10(-9)), 9 [DBH] (p-value?=?9.69?×?10(-9)) and 19 [CYP2A6/7] (p-value?=?3.49?×?10(-8)) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value?=?8.99?×?10(-9)), 4 [FAM13A] (p-value?=?3.88?×?10(-12)), 11 [MMP3/12] (p-value?=?3.29?×?10(-10)) and 14 [RIN3] (p-value?=?5.64?×?10(-9)).In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations.
Project description:We previously reported a progressive decline in absolute responses of FEV1 and FVC to a near-maximal dose of 2 different short-acting bronchodilators over 4 years. Since varying host factors and the method of expressing the response may impact the time trend of acute bronchodilator responses, we now examined the potential influence of salient host characteristics on changes in bronchodilator responses over time expressed in different ways.As part of the 4-year, placebo-controlled Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, pre- and post-bronchodilator spirometry was performed at baseline and 1 month and every 6 months thereafter. Post-bronchodilator values for FEV1 and FVC were analyzed for subjects completing at least the 1 year visit (Placebo - N?=?2463; Tiotropium - N?=?2579), stratified by GOLD stage, age, gender and smoking status and expressed as absolute, relative (%) and % predicted changes from pre-bronchodilator values. Annual changes in bronchodilator response were estimated using linear mixed effects models.For all subjects analyzed, FEV1 and FVC bronchodilator responses showed progressive and highly significant (p?<?0.0001) declines over 4 years. Declines were generally larger in patients with severe/very severe than mild/moderate airflow obstruction, in older patients (?65 yrs) and in former than continuing smokers.Acute FEV1 and FVC responses to bronchodilators decline significantly over time in COPD patients, whether expressed as absolute, relative or % predicted changes, potentially impacting on the clinical responses to bronchodilator therapy as well as on the annual rate of decline in post-bronchodilator lung function. Clinicaltrials.gov number: NCT00144339.
Project description:SETTING:The use of different spirometric definitions for chronic obstructive pulmonary disease (COPD) has made an informative review of the available prevalence surveys impossible. OBJECTIVE:To derive adjustment factors that allow the comparison of studies using different spirometric criteria. METHODS:Pre- and post-bronchodilator one-second forced expiratory volume (FEV1) and forced vital capacity (FVC) values were taken from the Burden of Obstructive Lung Disease (BOLD) survey in 16 centres. Using a post-bronchodilator FEV1/FVC ratio less than the lower limit of normal (LLN) as our reference prevalence, we calculated simple multiplicative adjustments to transform other reported prevalence estimates to reference values. These adjustments were then tested on independent data sets from six further BOLD centres and five centres from the PLATINO study, a Latin American survey on obstructive lung disease. RESULTS:Prevalence estimates based on pre-bronchodilator fixed-ratio measurements were 5-25% higher than reference values, and were strongly positively biased with age and prevalence level. Applying simple adjustments provided prevalence estimates that were almost unbiased and within 5% of the reference values. CONCLUSIONS:Using the BOLD data, we have been able to estimate COPD prevalences based on post-bronchodilator FEV1/FVC < LLN by adjusting estimates based on other common definitions, enabling more meaningful comparisons of published findings.
Project description:The relationship between patient-reported symptoms and objective measures of lung function is poorly understood.To determine the association between responsiveness to bronchodilator and respiratory symptoms in random population samples.4669 people aged 40 years and older from 8 sites in Canada completed interviewer-administered respiratory questionnaires and performed spirometry before and after administration of 200 ug of inhaled salbutamol. The effect of anthropometric variables, smoking exposure and doctor-diagnosed asthma (DDA) on bronchodilator responsiveness in forced expiratory volume in 1 second (FEV1) and in forced vital capacity (FVC) were evaluated. Multiple logistic regression was used to test for association between quintiles of increasing changes in FEV1 and in FVC after bronchodilator and several respiratory symptoms.Determinants of bronchodilator change in FEV1 and FVC included age, DDA, smoking, respiratory drug use and female gender [p<0.005 to p<0.0001 ]. In subjects without doctor-diagnosed asthma or COPD, bronchodilator response in FEV1 was associated with wheezing [p for trend<0.0001], while bronchodilator response for FVC was associated with breathlessness. [p for trend <0.0001].Bronchodilator responsiveness in FEV1 or FVC are associated with different respiratory symptoms in the community. Both flow and volume bronchodilator responses are useful parameters which together can be predictive of both wheezing and breathlessness in the general population.
Project description:The benefits of pharmacotherapy with tiotropium HandiHaler 18??g for patients with chronic obstructive pulmonary disease (COPD) have been previously demonstrated. However, few data exist regarding the treatment of moderate disease (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II).To determine whether tiotropium improves lung function/patient-reported outcomes in patients with GOLD stage II COPD naive to maintenance therapy.A randomised 24-week double-blind placebo-controlled trial of tiotropium 18??g once daily (via HandiHaler) was performed in maintenance therapy-naive patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 and post-bronchodilator FEV1 ?50 and <80%.A total of 457 patients were randomised (238 tiotropium, 219 placebo; mean age 62 years; FEV1 1.93?l (66% predicted)). Tiotropium was superior to placebo in mean change from baseline in post-dose FEV1 area under the curve from 0 to 3?h (AUC0-3h) at week 24 (primary endpoint): 0.19 vs. -0.03?l (least-squares mean difference 0.23?l, P<0.001). FVC AUC0-3h, trough and peak FEV1 and FVC were significantly improved with tiotropium versus placebo (P<0.001). Compared with placebo, tiotropium provided numerical improvements in physical activity (P=NS). Physician's Global Assessment (health status) improved (P=0.045) with less impairment on the Work Productivity and Activity Impairment questionnaire (P=0.043) at week 24. The incidence of exacerbations, cough, bronchitis and dyspnoea was lower with tiotropium than placebo.Tiotropium improved lung function and patient-reported outcomes in maintenance therapy-naive patients with GOLD stage II COPD, suggesting benefits in initiating maintenance therapy early.
Project description:The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD.Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.
Project description:Certain transient receptor potential (TRP) channels including <i>TRPM8</i> and <i>TRPA1</i> are widely expressed in the respiratory tract and have been shown to be the receptors of cigarette smoke and particulate matter-the main causative factors of chronic obstructive pulmonary disease (COPD). The aim of the study was to investigate the effect of <i>TRPM8</i> and <i>TRPA1</i> polymorphisms on COPD predisposition and lung function in COPD patients. The study enrolled 143 COPD patients and 104 smokers with post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 70%. Lung function was measured by spirometry. <i>TRPM8</i> and <i>TRPA1</i> polymorphisms were genotyped by LATE-PCR. None of the polymorphisms significantly influenced COPD predisposition after correction for covariates and multiple testing. Among COPD patients, the TT genotype of <i>TRPA1</i> rs7819749 was significantly associated with higher degree of bronchial obstruction. In addition, we established that carriers of the C allele of <i>TRPM8</i> rs11562975 more commonly had post-bronchodilator FEV1 < 60% (OR 3.2, 95%CI (1.14-8.94), <i>p</i> = 0.03) and revealed the effect of <i>TRPA1</i> rs959976 and <i>TRPM8</i> rs17865682 on bronchodilator response in COPD. Thus, the obtained results suggest possible involvement of <i>TRPM8</i> and <i>TRPA1</i> in COPD pathogenesis, indicating the necessity to further investigate their functional role in this pathology.