Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects.

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 × 10-8) and PPP4R4/SERPINA1 (P = 1.01 × 10-8) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ∼0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility. OBJECTIVES: To identify coding variants associated with COPD. METHODS: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts. MEASUREMENTS AND MAIN RESULTS: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. CONCLUSIONS: In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.

Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP.

Multiple intergenic single-nucleotide polymorphisms (SNPs) near hedgehog interacting protein (HHIP) on chromosome 4q31 have been strongly associated with pulmonary function levels and moderate-to-severe chronic obstructive pulmonary disease (COPD). However, whether the effects of variants in this region are related to HHIP or another gene has not been proven. We confirmed genetic association of SNPs in the 4q31 COPD genome-wide association study (GWAS) region in a Polish cohort containing severe COPD cases and healthy smoking controls (P = 0.001 to 0.002). We found that HHIP expression at both mRNA and protein levels is reduced in COPD lung tissues. We identified a genomic region located ∼85 kb upstream of HHIP which contains a subset of associated SNPs, interacts with the HHIP promoter through a chromatin loop and functions as an HHIP enhancer. The COPD risk haplotype of two SNPs within this enhancer region (rs6537296A and rs1542725C) was associated with statistically significant reductions in HHIP promoter activity. Moreover, rs1542725 demonstrates differential binding to the transcription factor Sp3; the COPD-associated allele exhibits increased Sp3 binding, which is consistent with Sp3's usual function as a transcriptional repressor. Thus, increased Sp3 binding at a functional SNP within the chromosome 4q31 COPD GWAS locus leads to reduced HHIP expression and increased susceptibility to COPD through distal transcriptional regulation. Together, our findings reveal one mechanism through which SNPs upstream of the HHIP gene modulate the expression of HHIP and functionally implicate reduced HHIP gene expression in the pathogenesis of COPD.

CHRNA3/5, IREB2, and ADCY2 are associated with severe chronic obstructive pulmonary disease in Poland.

We examined the association between single-nucleotide polymorphisms (SNPs) previously associated with chronic obstructive pulmonary disease (COPD) and/or lung function with COPD and COPD-related phenotypes in a novel cohort of patients with severe to very severe COPD. We examined 315 cases of COPD and 330 Caucasian control smokers from Poland. We included three SNPs previously associated with COPD: rs7671167 (FAM13A), rs13180 (IREB2), and rs8034191 (CHRNA 3/5), and four SNPs associated with lung function in a genome-wide association study of general population samples: rs2070600 (AGER), rs11134242 (ADCY2), rs4316710 (THSD4), and rs17096090 (INTS12). We tested for associations with severe COPD and COPD-related phenotypes, including lung function, smoking behavior, and body mass index. Subjects with COPD were older (average age 62 versus 58 years, P < 0.01), with more pack-years of smoking (45 versus 33 pack-years, P < 0.01). CHRNA3/5 (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.5-2.4; P = 7.4 × 10(-7)), IREB2 (OR, 0.69; 95% CI, 0.5-0.9; P = 3.4 × 10(-3)), and ADCY2 (OR, 1.35; 95% CI, 1.1-1.7; P = 0.01) demonstrated significant associations with COPD. FAM13A (OR, 0.8; 95% CI, 0.7-1.0; P = 0.11) approached statistical significance. FAM13A and ADCY2 also demonstrated a significant association with lung function. Thus, in severe to very severe COPD, we demonstrate a replication of association between two SNPs previously associated with COPD (CHRNA3/5 and IREB2), as well as an association with COPD of one locus initially associated with lung function (ADCY2).

[The coexistence of the impaired exercise tolerance in patients with obstructive sleep apnea with gastroesophageal reflux]. / Wspoltistnienie obnizonej wydolosci wysilkowej chorych na obturacyjny bezdech senny z wystepowaniem refluksu zoladkowo-przelykowego.

INTRODUCTION: Gastroesophageal reflux (GERD) is a frequent disease in patients with obstructive sleep apnea (OSA). The aim of the study was to evaluate possible correlation between the impairement of exercise tolerance and GERD. MATERIAL AND METHODS: We examined 18 patients with OSA, mean AHI - 44 +/- 22; 6 females, 12 males, mean age 55 +/- 9 years. All patients were treated for metabolic disorders and for hypertension or coronary artery disease. In all patients gastroscopy was performed with 24h pHmetry and 6MWT. RESULTS: In 12 patients GERD was found, in 14 patients esophagitis was diagnosed (among them there were 3 patients without GERD). Patients with GERD were younger (53 +/- 7 vs. 59 +/- 11 years) and more obese (BMI - 38 +/- 5 vs. 36 +/- 9 kg/m(2)). During 6MWT the distance covered was shorter (in % of normal values) in GERD subjects: 78 +/- 17 vs. 86 +/- 22%) and desaturation was deeper (91 +/- 3 vs. 94 +/- 3%). CONCLUSIONS: Despite some tendencies the relationship between GERD and impairement of exercise tolerance in OSA patients was not statistically significant. Perhaps study in larger group of subjects will be more reliable.

[A 30-year history of a patient with bronchiectasis]. / Trzydziestoletnia obserwacja chorego na rozstrzenie oskrzeli.

We describe the long-term course of a patient with bronchiectasis. Sequential chest X-rays, symptoms, spirometry and blood gas analysis obtained during the observation period showed gradual progression. Conservative medical management was implemented in the treatment of described patient. Bronchiectasis is a disease characterised by irreversible dilation of airways, repeated respiratory infections, productive cough and dyspnoea caused by a variety of factors. The foundations of therapy include administration of antibiotics, treatment of underlying conditions, bronchial hygiene and rarely--surgery. Survival in bronchiectasis depends on presence of comorbidities and complications of lung disease.

Severe COPD cases from Korea, Poland, and USA have substantial differences in respiratory symptoms and other respiratory illnesses.

PURPOSE: Chronic obstructive pulmonary disease (COPD), characterized by irreversible airflow obstruction, is a major cause of morbidity and mortality worldwide. However, geographic differences in the clinical characteristics of severe COPD patients have not been widely studied. METHODS: We recruited a total of 828 severe COPD cases from three continents. Subjects in Poland were enrolled by the Institute of Tuberculosis and Lung Diseases in Warsaw; subjects in Korea participated at several university hospitals in Korea; and subjects in USA were enrolled at two clinics affiliated with academic medical centers. All subjects were over the age of 30 with at least 10 pack-years of cigarette smoking history. Cases manifested severe to very severe airflow obstruction with post-bronchodilator forced expiratory volume in 1 second (FEV1) <50% predicted and FEV1/forced vital capacity <0.7. All subjects completed a detailed questionnaire and underwent standardized pre-bronchodilator and post-bronchodilator spirometry. Subjects with known tuberculosis (TB)-associated lung parenchymal destruction were excluded. Univariate and multivariate assessments of the impact of the country of origin on respiratory symptoms and respiratory illness were performed. RESULTS: In both univariate and multivariate analyses, a history of TB (38.7%) and physician-diagnosed asthma (43.9%) were significantly more common in subjects with severe COPD from Korea than USA or Poland, while attacks of bronchitis (64.2%) were more common in subjects with severe COPD from Poland. COPD subjects from Poland had more severe dyspnea (modified Medical Research Council 3.3±1.0) and more frequently reported symptoms of chronic bronchitis (52.2%). A history of TB was also more common in Poland (10.8%) than in USA (0.3%) severe COPD patients. CONCLUSION: Respiratory symptoms and other respiratory illnesses associated with severe COPD differed widely among three continents.

[Gastroesophageal reflux disease (GERD) in patients with obstructive sleep apnoea syndrome (OSAS)]. / Refluks zoladkowo-przelykowy u chorych na obturacyjny bezdech senny (OBS).

Gastroesophageal reflux disease (GERD) is a common cause of chronic cough, heartburn, epigastric or retrosternal discomfort, chest pain and abdominal pain or esophagitis. Our patients with OSAS seldom manifest GERD symptoms. We suspected that obesity and high pressure in abdominal cavity may induce acid gastroesophageal reflux in these patients. The aim of the study was to test the hypothesis that obesity, cigarettes smoking or ventilatory and gas exchange abnormalities provoke GERD. We studied 21 consecutive patients with severe OSAS (mean AHI 44.9+/-23.8) before CPAP treatment, all without GERD clinical symptoms. Standard polysomnography, gastroscopy and 24-h oesophageal pH monitoring was performed. There were 6 females, 15 males, mean age 57+/-9 years, mean BMI 38+/-6 kg/m2. All patients presented with normal spirometric and gas exchange values (mean VC 3.64+/-1.23 1, 90% of normal, mean FEV1 2.61+/-0.95 1, 83% of normal, mean FEV1%VC 72%, mean PaO2 68.1+/-7.7 mmHg, mean PaCO2 40.8+/-5.8 mmHg, mean pH 7.42+/-0.02). GERD was diagnosed in 14 patients. Patients with GERD were younger, more often were cigarettes smokers (5/14). We did not fi nd statistically significant differences between severity of OSAS, BMI, ventilatory or gas exchange parameters and GERD.

[Effect of nocturnal hypoxaemia on the development of pulmonary hypertension in patients with COPD]. / Próba oceny wplywu hipoksemii nocnej na rozwój nadcisnienia plucnego u chorych na POChP.

Majority of subjects with severe COPD develop mild pulmonary hypertension. Those patients usually present with diurnal, resting hypoxaemia. Further hypoxaemic dips during sleep probably contribute to development permanent pulmonary hypertension. However, separation of effects of diurnal from nocturnal hypoxaemia is difficult. Correlations between severity of nocturnal hypoxaemia and pulmonary arterial pressure and pulmonary vascular resistance were week. There was no correlation between time spent in desaturation and pulmonary arterial pressure and pulmonary resistance.

[Solitary fibrous tumor of the pleura in 75-year old woman]. / Odosobniony guz wlóknisty oplucnej u 75-letniej chorej.

A 75-year-old asymptomatic woman with stable coronary heart disease presented tumor in lower left lobe on routine chest radiograph. A CT scan showed a large sharply delineated mass at this site (84 x 52 x 90 mm). There were no signs of infiltration, no abnormalities were seen in mediastinal structures and on the right side. The pedunculated tumor was resected during left thoracotomy (posterolateral incision). Histological examination revealed spindle-like cells and rich collagen net. Mitoses and necrosis were absent. Final diagnosis was: solitary fibrous tumor of the visceral pleura. During 7-year follow-up recurrence was not observed.

[The variability of clinical presentation of chronic obstructive pulmonary disease in patients with hereditary alpha-1 antitrypsin deficiency]. / Zmiennosc obrazu klinicznego przewleklej obturacyjnej choroby pluc u chorych z wrodzonym niedoborem alfa-1 antytrypsyny.

Four patients with alpha-1 antitrypsin (alpha-1 AT) deficiency are presented: one woman with severe (phenotype PiZ) and 3 men with moderate (phenotype PiMZ) deficiency of alpha-1 AT. The variability of clinical presentation of hereditary emphysema is described. In all patients tobacco smoking history, spirometric and 6-minutes walking tests as well as HRCT of the lung were performed and compared. The influence of smoking on the functional status is underlined.

[Pulmonary hypertension in patients with pure obstructive sleep apnea]. / Nadcisnienie plucne u chorych na niepowiklany obturacyjny bezdech senny.

UNLABELLED: Patients with obstructive sleep apnoea (OSA) every night experience recurrent episodes of alveolar hypoxia. Alveolar hypoxia is the most potent pulmonary vasoconstrictor causing remodeling of pulmonary arteries and pulmonary hypertension. Development of pulmonary hypertension in patients with OSA is rather rarely observed but still discussed. We studied pulmonary haemodynamics, using Swan Ganz thermodilution catheter, in 67 patients (64 M and 3 F, mean age 45 years) with severe OSA (in full polysomnography mean AHI = 62) and normal pulmonary function data. We observed normal mean haemodynamic values at rest: PPA 15,8 mm Hg, PW 6.8 mm Hg, CO 5.6 L/min. PVR 150 dyn.sec.cm(-5). In 11 pts (16%) the pulmonary artery pressure at rest was elevated (PPA 23.9 mm Hg and PVR 234 dyn.sec.cm(-5)), they were younger, more obese and had higher number of apneic episodes per hour of sleep. During mild exercise (44 pts) PPA rose from 15.8 mm Hg to 29.8 mm Hg and was abnormally high in 17 pts. IN CONCLUSION: we observed pulmonary hypertension at rest in 16% patients with severe OSA, but during exercise in about 40%.