Mendelian randomization study of interleukin-6 in chronic obstructive pulmonary disease.

BACKGROUND: Cross-sectional studies have demonstrated that increased levels of interleukin-6 (IL6) are present in the airways and blood samples of patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To investigate the association between IL6 and the risk of COPD using a Mendelian randomization approach. METHODS: Eight common single-nucleotide polymorphisms (SNPs) in the region of the IL6 gene were genotyped using both TaqMan and Illumina in the Rotterdam Study, a prospective population-based cohort study consisting of 7,983 participants aged 55 years or older, including 928 COPD patients. At baseline, blood was drawn in a random sample of 714 subjects to measure the IL6 plasma level. Analysis of variance, logistic regression, and Cox proportional hazard models--adjusted for age, gender, pack years, and BMI--were used for analyses. RESULTS: High levels of IL6 (>2.4 pg/ml, the highest tertile) were associated with a three-fold increased risk of developing COPD, in comparison to low levels (<1.4 pg/ml, the lowest tertile). The rs2056576 SNP was associated with a 10% increase in the risk of COPD per additional T allele. However, the association was no longer significant after adjustment. No association was found with other common SNPs in the IL6 gene and COPD. CONCLUSIONS: Although increased IL6 plasma levels at baseline are associated with the risk of developing COPD during follow-up, there was no strong evidence for an association between common variation in the IL6 gene and the risk of COPD.

Neomacrolides in the treatment of patients with severe asthma and/or bronchiectasis: a retrospective observational study.

RATIONALE: Previous studies have demonstrated that long-term low-dose macrolides are efficacious in cystic fibrosis (CF) and diffuse panbronchiolitis, two chronic neutrophilic airway diseases. AIMS: The aims of this study were to evaluate the efficacy and safety of low-dose neomacrolides as add-on therapy in patients with severe asthma and/or bronchiectasis and to identify predictors for therapeutic response. METHODS: In a retrospective observational cohort study, we examined 131 adult, non-CF patients with severe asthma and/or bronchiectasis, receiving low-dose neomacrolides as add-on treatment. Pulmonary function tests and symptom scores were assessed at baseline and after 3 to 8 weeks of therapy. RESULTS: After 3-8 weeks of treatment with low-dose neomacrolides, 108 patients were available for evaluation. In asthma patients (n = 47), pulmonary function tests and symptom scores improved significantly. Responders (≥7% forced expiratory volume in one second predicted [FEV(1)%] improvement) were older (55 vs. 47 years; p = 0.042) and had a longer duration of asthma (29 vs. 9 years; p = 0.052). In patients with bronchiectasis only (n = 61), symptom scores improved significantly. Responders (≥60% symptom score improvement) were older (61 vs. 53 years; p = 0.004), more frequently male (53% vs. 27%; p = 0.043), and there was a nonsignificant trend towards higher high-resolution CT (HRCT) score for bronchiectasis in responders (6.4 vs. 4.6; p = 0.053). In multivariate logistic regression analysis, age and male gender were independent predictors for improvement in this group. CONCLUSION: The results of this retrospective study suggest that neomacrolides may be useful as an add-on therapy in patients with severe asthma and/or bronchiectasis. Older age may predict good response in patients with severe asthma, whereas older age, male gender and a higher HRCT score for bronchiectasis may predict therapeutic response in patients with bronchiectasis only. Prospective controlled trials of neomacrolides in patients with severe asthma are needed to confirm these observations.

MicroRNA expression in induced sputum of smokers and patients with chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by progressive inflammation in the airways and lungs combined with disturbed homeostatic functions of pulmonary cells. MicroRNAs (miRNAs) have the ability to regulate these processes by interfering with gene transcription and translation. OBJECTIVES: We aimed to identify miRNA expression in induced sputum and examined whether the expression of miRNAs differed between patients with COPD and subjects without airflow limitation. METHODS: Expression of 627 miRNAs was evaluated in induced sputum supernatant of 32 subjects by stem-loop reverse transcription-quantitative polymerase chain reaction. Differentially expressed miRNAs were validated in an independent replication cohort of 41 subjects. Enrichment of miRNA target genes was identified by in silico analysis. Protein expression of target genes was determined by ELISA. MEASUREMENTS AND MAIN RESULTS: Thirty-four miRNAs were differentially expressed between never-smokers and current smokers without airflow limitation in the screening cohort. Eight miRNAs were expressed at a significantly lower level in current-smoking patients with COPD compared with never-smokers without airflow limitation. Reduced expression of let-7c and miR-125b in patients with COPD compared with healthy subjects was confirmed in the validation cohort. Target genes of let-7c were significantly enriched in the sputum of patients with severe COPD. The concentration of tumor necrosis factor receptor type II (TNFR-II, implicated in COPD pathogenesis and a predicted target gene of let-7c) was inversely correlated with the sputum levels of let-7c . CONCLUSIONS: let-7c is significantly reduced in the sputum of currently smoking patients with COPD and is associated with increased expression of TNFR-II.

Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.

Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

Prevalence, incidence, and lifetime risk for the development of COPD in the elderly: the Rotterdam study.

BACKGROUND: COPD is a major cause of chronic morbidity and mortality throughout the world. Although the prevalence of COPD is already well documented, there are only few studies regarding the incidence of COPD. METHODS: In a prospective population-based cohort study among subjects aged >or= 55 years, COPD was diagnosed with an algorithm based on the validation of hospital discharge letters, files from the general practitioner, and spirometry reports. RESULTS: In this study cohort of 7,983 participants, 648 cases were identified with incident COPD after a median follow-up time of 11 years (interquartile range, 7.8 years). This resulted in an overall incidence rate (IR) of 9.2/1,000 person-years (PY) [95% confidence interval (CI), 8.5 to 10.0]. The IR of COPD was higher among men (14.4/1,000 PY; 95% CI, 13.0 to 16.0) than among women (6.2/1,000 PY; 95% CI, 5.5 to 7.0), and higher in smokers than in never-smokers (12.8/1,000 PY; 95% CI, 11.7 to 13.9 and 3.9/1,000 PY; 95% CI, 3.2 to 4.7, respectively). Remarkable was the high incidence in the youngest female age category of 55 to 59 years (7.4/1,000 PY; 95% CI, 4.1 to 12.6). For a 55-year-old man and woman still free of COPD at cohort entry, the risk for the development of COPD over the coming 40 years was 24% and 16%, respectively. CONCLUSION: The overall incidence of COPD in an elderly population is 9.2/1,000 PY, with a remarkably high incidence in the youngest women, suggesting a further shift toward the female sex in the gender distribution of COPD. During their further lives, one of four men and one of six women free of COPD at the age of 55 years will have COPD develop.

C-reactive protein levels, haplotypes, and the risk of incident chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by substantial chronic inflammation in the pulmonary compartment as well as in the systemic circulation. OBJECTIVES: To investigate potentially causal association, we examined whether serum levels of high-sensitivity C-reactive protein (hsCRP) and variations in the CRP gene are associated with the risk of developing COPD. METHODS: This study is part of the Rotterdam Study, a prospective population-based cohort study among subjects aged 55 years or older. At baseline, 6,836 subjects without COPD had a blood sample available for assessment of hsCRP serum levels and haplotypes of the CRP gene. We analyzed the association between hsCRP levels, CRP gene haplotypes, and incident COPD with Cox proportional hazard models, adjusted for age, sex, and other confounders. MEASUREMENTS AND MAIN RESULTS: High levels of hsCRP (>3 mg/L) were associated with a significantly increased risk of incident COPD (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.16-2.49) compared with persons with low levels (<1 mg/L). The risk remained increased after adjusting for potential confounders and introducing a latency period of 3 years. The risk was most pronounced in former smokers (HR, 2.2; 95% CI, 1.12-3.74). hsCRP was not a risk factor in never smokers. No CRP single nucleotide polymorphism or haplotype was associated with a significantly increased or decreased COPD risk. CONCLUSIONS: Increased hsCRP levels are predictive for the occurrence of COPD in smokers. However, haplotypes of the CRP gene, which influence hsCRP levels, are not associated with an altered risk of developing COPD.