Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide(1). We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 x 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples(2-7), while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis(8,9) (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity(10). We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases

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.

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 ¼ 7.4 3 10 27 ), IREB2 (OR, 0.69; 95% CI, 0.5-0.9; P ¼ 3.4 3 10 23 ), and ADCY2 (OR, 1.35; 95% CI, 1.1-1.7; P ¼ 0.01) demonstrated significant associations with COPD. FAM13A (OR, 0.8; 95% CI, 0.7-1.0; P ¼ 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).Keywords: chronic obstructive pulmonary disease; genetic association analysis; lung function; smoking; nicotine addiction Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, and its prevalence continues to grow (1). Although cigarette smoking is the most significant risk factor for COPD, cigarette smoking differentially affects lung function decline, and not all smokers will develop COPD (2). The individual response to cigarette smoke and other environmental factors is affected in part by genetic factors, and the development of COPD is the culmination of the environment acting in concert with a complex array of genetic traits (3).Although the development of COPD is mediated by multiple genetic factors, to date few susceptibility genes other than a 1 -antitrypsin (SERPINA1) have been convincingly identified.Early candidate gene studies yielded inconsistent results (4). These studies were limited by small sample sizes and a lack of uniformity in COPD phenotypes, including the degree of airflow obstruction and intensity of smoking exposure in subjects examined. However, several recent genome-wide association studies (GWAS) have identified genomic regions that demonstrate a highly significant and reproducible association with COPD in large studies including subjects with a range of impaired lung function and smoking history. These GWAS regions are located in FAM13A on chromosome 4q22 (5), on chromosome 4q31...

Pulmonary haemodynamics at rest and during exercise was studied in 30 patients with histologically confirmed sarcoidosis. All subjects were divided into three groups according to the stage of the disease assessed by radiological image of pulmonary lesions. At rest, in stage I and II patients, the mean pulmonary pressure (P_AP) was normal. In stage IIIpatients, a slight pulmonary hypertension was found. During exercise, a rise in Pap in stage I and II subjects was within the normal limits for a given workload, although in individual stage IIsubjects a rise in P_AP was abnormally high. In all stage IIIpatients a rise in Pap was pathologically elevated

Background. Alveolar hypoxia is the most important mechanism leading to pulmonary arterial vasoconstriction, remodelling and pulmonary hypertension. Patients with Obstructive Sleep Apnoea Syndrome (OSAS) experience multiple short periods of alveolar hypoxia during apnoeic episodes. However, the question as to whether these hypoxic episodes are responsible for the development of permanent pulmonary hypertension is still debatable. We aimed to investigate the relationship between the episodes of nocturnal desaturation and pulmonary haemodynamics in two distinct group patients: with pure OSAS or an overlap syndrome. Methods: We studied 67 patients with severe OSAS (means: age 45±8 years, AHI 62±22, FEV1 3.6±0.8 L = 97±16% of predicted PaO2 72±10 mmHg, PaCO2 40±4 mmHg) and 17 patients with an overlap syndrome (OS), means: age 51±5 years, AHI 64±19, FEV1 1.5±0.7 = 43±16% of predicted PaO2 57±9 mmHg). All subjects underwent pulmonary artery catheterisation with pressure and flow recordings and an overnight full sleep study. Results. On average patients with OSAS had nocturnal desaturation (mean overnight SaO2 = 87±5%) and normal PPA (15.8±4.6 mmHg). Only 11 out of 67 subjects (16%) presented with pulmonary hypertension. Patients with OS had nocturnal desaturation (mean overnight SaO2 = 80.2±8.5%) and mild pulmonary hypertension (PPA 24.2±7.4 mmHg). Only three out of 17 patients had normal pulmonary arterial pressure. Conclusions. In patients with severe OSAS, pulmonary hypertension is rare (16%) and is related best to the severity of the disease and to obesity. In OS patients diurnal pulmonary hypertension is frequent but does not correlate with the severity of nocturnal desaturation.