Pulmonary Disease, Chronic Obstructive

Description

Chronic obstructive pulmonary disease (COPD) is a common, complex disorder associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction due to chronic bronchitis, emphysema, and/or small airways disease. Airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) (Silverman et al., 2002; Celedon et al., 2004).

Mapping

Linkage to Chromosome 2q

Silverman et al. (2002) performed an autosomal 10-cM genomewide scan of short tandem repeat polymorphic markers in 72 pedigrees (585 individuals) ascertained through probands with severe early-onset COPD. In an initial genomewide scan, significant evidence for linkage of FEV1/FVC to 2q was found; lod score = 4.12 at 222 cM. Suggestive evidence was found for linkage of FEV1/FVC to chromosome 1 (lod score = 1.92 at 120 cM) and chromosome 17 (lod score = 2.03 at 67 cM) and linkage of FVC on chromosome 1 (lod score = 2.05 at 13 cM). The highest lod score for FEV1 in the initial genomewide scan was 1.53, on chromosome 12, at 36 cM. After inclusion of 12 additional STR markers on 12p, which had been previously genotyped in this population, suggestive evidence for linkage of FEV1 (lod score = 2.43 at 37 cM) to this region was demonstrated. These observations provided both significant evidence for an early-onset COPD-susceptibility locus on chromosome 2 and suggestive evidence for linkage of spirometry-related phenotypes to several other genomic regions.

Palmer et al. (2003) performed a 9-cM genome scan in 560 members of 72 pedigrees ascertained through probands with severe, early-onset COPD. Multipoint variance component linkage analysis was performed for quantitative phenotypes including bronchodilator responsiveness measures and postbronchodilator FEV1 and FEV1/FVC. Postbronchodilator FEV1 was linked to multiple regions, most significantly to markers on chromosome 8p (lod = 3.30) and 1p (lod = 2.24). Postbronchodilator FEV1/FVC was also linked to multiple regions, most significantly to markers on chromosome 2q (lod = 4.42) and 1p (lod = 2.52). When compared with prebronchodilator spirometric indices, the postbronchodilator values demonstrated increased evidence of linkage in multiple genomic regions. In particular, the lod score for the 8p linkage to FEV1 approximately doubled from 1.58 to 3.30. Palmer et al. (2003) concluded that there is significant linkage of airflow obstruction susceptibility to loci on chromosomes 2q and 8p and that postbronchodilator spirometric measures may be optimal phenotypes for COPD genetic studies.

DeMeo et al. (2006) undertook to identify a specific gene on 2q that might be responsible for the linkage results found by Silverman et al. (2002) and Palmer et al. (2003) in the Boston Early-Onset COPD Study. By integrating results from microarray studies of murine lung development and microarray studies of human COPD gene expression with human COPD linkage results on 2q, they identified SERPINE2 (177010) as a positional candidate susceptibility gene for COPD. Immunohistochemistry demonstrated expression of SERPINE2 protein in mouse and human adult lung tissue. In family-based association testing of 127 severe, early-onset COPD pedigrees from the Boston Early-Onset COPD Study, they observed significant association with COPD phenotypes and 18 single-nucleotide polymorphisms (SNPs) in the SERPINE2 gene. These and other results suggested that SERPINE2 is a COPD susceptibility gene and is likely influenced by gene-by-smoking interaction.

Chappell et al. (2006) were unable to replicate the observations of DeMeo et al. (2006) in a more highly powered case-control study. They suggested that differences in the disease phenotype of the patients studied may account for this, as the study by Chappell et al. (2006) included patients with and without emphysema.

Association Studies

Joos et al. (2002) found an association of a SNP in the matrix metalloproteinase-1 gene (MMP1; 120353.0001) on chromosome 11q22-q23 with the rate of decline of lung function in COPD.

In 103 patients with COPD, Eddahibi et al. (2003) determined the 5-HTTLPR genotype (182138.0001) and measured pulmonary artery pressure. They found that patients carrying the LL genotype, which is associated with higher levels of 5-HTT expression in pulmonary artery smooth muscle cells than the LS and SS genotypes, had more severe pulmonary hypertension than LS or SS patients (p less than 0.01). Eddahibi et al. (2003) concluded that the 5-HTTLPR genotype appears to determine the severity of pulmonary hypertension in patients with COPD.

Celedon et al. (2004) performed association analysis between SNPs in the TGFB1 gene (190180) and COPD phenotypes in a family-based sample and a case-control study. Stratification by smoking status substantially improved the evidence of linkage to chromosome 19q for COPD phenotypes. Among former and current smokers in the study, there was significant evidence of linkage between chromosome 19q and prebronchodilator (pre-BD) FEV1 (lod = 3.30). In these families, 3 SNPs in TGFB1 were significantly associated with pre- and post-BD FEV1 (p less than 0.05). Among smokers in the COPD cases and control subjects, 3 SNPs in TGFB1 were significantly associated with COPD (p less than or equal to 0.02 in all cases). Celedon et al. (2004) concluded that chromosome 19q likely contains a genetic locus (or loci) that influences COPD through an interaction with cigarette smoking.

DeMeo et al. (2009) tested 889 SNPs for association with COPD in 389 patients with severe COPD and 424 cigarette-smoking controls. They identified 71 SNPs with at least nominal association with COPD susceptibility; those 71 SNPs were then evaluated in a family-based study of 127 probands with severe, early-onset COPD and 822 of their family members. Combining p values from the case-control and family-based analyses and using 5.60 x 10(-5) as a 'conservative' threshold for significance, DeMeo et al. (2009) found 3 SNPs in the IREB2 gene on chromosome 15q25.1 (rs2568494, rs2656069, and rs10851906) with significant association. The association was confirmed in a family-based study of 3,117 additional individuals, with combined p values across all cohorts for COPD ranging from 1.65 x 10(-5) to 1.64 x 10(-7) for the 3 most strongly associated SNPs. The authors also found that IREB2 protein and mRNA were increased in lung tissue samples from COPD patients compared to controls.

Hunninghake et al. (2009) tested for an association between SNPs in the MMP12 gene (601046) on chromosome 11q22 and FEV1 in more than 8,300 subjects in 7 cohorts that included children and adults. They found that the minor allele (G) of rs2276109 was associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele was also associated with a reduced risk of COPD in adult smokers. Hunninghake et al. (2009) noted that this minor allele has been associated with decreased promoter activity through less efficient binding of AP1 (165160) in both murine and human monocytic cell lines (Jormsjo et al., 2000) and that deletion of the AP1 binding site abolishes both basal and stimulated expression of MMP12 (Wu et al., 2003).

Upon activation by a broad range of stimuli, the TRPV4 (605427) cation channel functions to control airway epithelial cell volume and epithelial and endothelial permeability; it also triggers bronchial smooth muscle contraction and participates in autoregulation of mucociliary transport. Zhu et al. (2009) genotyped 2 independent Caucasian populations at 20 SNPs in the TRPV4 gene on chromosome 12q24.1 and tested qualitative COPD and quantitative FEV1 and FEV1/FVC phenotypes. In a family-based study of 606 families and 1,891 patients, 7 of 20 SNPs tested were associated with COPD (p values ranging from 2.5 x 10(-4) to 0.04), and 6 SNPs were associated with FEV1/FVC (p values ranging from 0.02 to 0.03). In a case-control study of 953 patients and 956 controls, 4 of 7 SNPs associated with COPD demonstrated replicated associations with the same effect directions (p values ranging from 0.02 to 0.03). Significant haplotype associations supported the results of the single SNP analysis.

The most widely recognized candidate gene in COPD is SERPINA1 (107400), although it has been suggested that the SERPINA3 gene (107280) may play a role. To detect cryptic genetic variants that might contribute to disease, Chappell et al. (2006) identified 15 SNP haplotype tags from high-density SNP maps of the 2 genes and evaluated these SNPs in a large case-control genetic study of COPD; the study consisted of 1,018 COPD cases and 911 controls living in England, Scotland, Ireland, Holland, Italy, and Spain. For SERPINA1, 6 newly identified haplotypes with a common backbone of 5 SNPs were found to increase the risk of disease by 6- to 50-fold, the highest risk of COPD reported to that time. In contrast, no haplotype associations for SERPINA3 were identified.

Cho et al. (2010) performed a genomewide association study for COPD in 3 population cohorts involving a total of 2,940 cases and 1,380 controls who were current or former smokers with normal lung function, and found the strongest association with 2 SNPs in linkage disequilibrium within the FAM13A gene on chromosome 4q22.1, rs1903003 and rs7671167. The association was replicated in a case-control group and 2 family-based cohorts (combined p = 9.47 x 10(-11) and 1.22 x 10(-11) for rs1903003 and rs7671167, respectively). The SNPs were not associated with pack-years of cigarette smoking in cases or controls. Cho et al. (2010) noted that the SNPs lie in an intronic region downstream of a Rho GTPase-activating protein (RhoGAP) domain.

Castaldi et al. (2010) conducted a systematic review and metaanalysis of all population-based, case-control candidate gene COPD studies indexed in PubMed before July 16, 2008. Findings were stored in an online database, which served as an up-to-date compendium of COPD genetic associations and cumulative metaanalysis estimates. Although the vast majority of COPD candidate gene era studies are underpowered to detect genetic effect odds ratios of 1.2 to 1.5, the authors identified 27 genetic variants with adequate data for quantitative metaanalysis. Of these variants, 4 were significantly associated with COPD susceptibility in random effects metaanalysis, the GSTM1 (138350) null variant, rs1800470 in the TGFB1 gene (190180), rs1800629 in the TNF gene (191160), and rs1799896 in the SOD3 gene (185490).

Among 742 patients with COPD and 4,976 controls from the Rotterdam study who were genotyped for an A-to-G transition in rs13118928 on chromosome 4q31 near the HHIP gene (606178), van Durme et al. (2010) found an association between genotype and disease. The minor G allele was protective, with heterozygotes having an OR of 0.80 and homozygotes an OR of 0.60. A metaanalysis of several previously published studies also found a significant association between the G allele and protection against COPD (p value of 3.4 x 10(-9)). Van Durme et al. (2010) noted that the hedgehog signaling pathway plays an important role in lung morphogenesis and cellular responses to lung injury.

Zhou et al. (2012) confirmed the association between rs13118928 on chromosome 4q31 and COPD in a study of 315 patients with severe COPD and 330 smoking controls in Poland (OR of 0.68 for the G allele, p = 0.002). This SNP occurs in an intergenic region about 51 kb from HHIP.

Pathogenesis

Lee et al. (2007) studied the immune responses of age-matched smokers with and without emphysema and found that differential responsiveness of T cells to elastin (ELN; 130160) peptides, but not to collagen (see COL6A1; 120220) or albumin (ALB; 103600), correlated with emphysema severity. Compared with controls, COPD patients secreted increased levels of IFNG (147570) and IL10 (124092) in response to elastin peptides in an MHC II-dependent manner. Antibody to elastin, but not to collagen, was also increased in emphysema patients, as were lung B cells secreting antibody to the protein. Although regulatory T cell (Treg) responses did not differ between subject and control peripheral blood cells, emphysema patients showed a significant reduction of lung Tregs compared with controls. Lee et al. (2007) concluded that antielastin autoimmunity, possibly resulting from secretion of proteolytic enzymes induced by cigarette smoke exposure, is associated with an inflammatory response leading to emphysema and to tobacco-related pathology in other organs.

By studying the lungs and sputa of nonsmokers, current smokers, and patients with COPD, all of whom were current or former smokers, Hwang et al. (2011) showed that FOXO3 (602681) levels were significantly decreased in smokers and COPD patients. Mice exposed to cigarette smoke also had reduced Foxo3 (see ANIMAL MODEL). Immunoblot and immunoprecipitation analyses of bronchial epithelial cells cultured with cigarette smoke extract demonstrated translocation of FOXO3 to the nucleus, where it interacted with RELA (164014) and inhibited NF-kappa-B (164011) DNA-binding activity. Hwang et al. (2011) concluded that FOXO3 has a significant role in the regulation of lung inflammation and in the pathogenesis of COPD and emphysema.

Zhou et al. (2012) found decreased levels of HHIP (606178) mRNA in lung tissue samples from 18 patients with COPD compared to 15 controls, and decreased HHIP protein levels in lung tissue from 12 patients with COPD compared to 7 controls. Sequencing of the HHIP gene and its upstream region in 29 patients with severe COPD identified a risk haplotype including a T-to-C transition in rs1542725 that was associated with the disorder (odds ratio of 0.68 for the T allele, p = 0.0017) and was associated with decreased HHIP promoter activity. The rs1542725 variant is located about 85 kb upstream of HHIP and was demonstrated to function as an HHIP regulator by binding to transcription factor SP3 (601804). The COPD-associated C allele showed stronger SP3 binding than the T allele, consistent with the role of SP3 as a 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. The study functionally implicated reduced HHIP gene expression in the pathogenesis of COPD.

Molecular Genetics

Among 201 smokers, Yamada et al. (2000) found an association between emphysema and a longer length polymorphism in the promoter region of the HMOX1 gene (141250.0003). The proportion of genotypic frequencies in the group with longer alleles was significantly higher in smokers with CPE than in smokers without CPE. These findings suggested that the large size of a (GT)n repeat in the HMOX1 gene promoter may reduce HMOX1 inducibility by reactive oxygen species in cigarette smoke, thereby resulting in the development of COPD.

Among 749 French adults, including 40% who never smoked, Guenegou et al. (2006) observed an association between carriers of the long (L) allele of the (GT)n polymorphism and decreased lung function, as assessed by forced expiratory volume in 1 second (FEV1) and FEV1/forced ventilatory capacity (FVC) ratio, over an 8-year period (1992 to 2000). At the 8-year follow-up, the mean annual FEV1 and FEV1/FVC declines in patients with 1 or 2 L alleles were -30.9 ml/year and -1.8 U/year, FEV1/FVC decline was steeper in L allele carriers than in noncarriers (-2.6 versus -1.5, p = 0.07). There was a strong interaction between the L allele and smoking. At the 8-year follow-up, the L allele was associated with lower FEV1 and FEV1/FVC in heavy smokers only. Baseline heavy smokers carrying the L allele showed the steepest FEV1 decline (-62.0 ml/year) and the steepest FEV1/FVC decline (-8.8 U/year) (p for interaction = 0.009 and 0.0006). Guenegou et al. (2006) suggested that a long HMOX1 gene promoter in heavy smokers is associated with susceptibility to develop airway obstruction. In a 25-year study, Siedlinski et al. (2008) replicated the findings of Guenegou et al. (2006) in a large Dutch population of 1,390 individuals, including 67.9% who never smoked.

Animal Model

Using a mouse model of chronic lung disease linked to an initial acute response to Sendai virus (similar to human paramyxoviruses such as respiratory syncytial virus), Kim et al. (2008) showed that after viral clearance, the inflammatory response is driven by IL13 produced by macrophages stimulated by CD1d (188410)-dependent T cell receptor-invariant natural killer T (NKT) cells. Airway hyperreactivity and mucous cell metaplasia did not occur after IL13 blockade or in Il13 -/-, CD1d -/-, or NKT-deficient mice. Immunohistochemical analysis in human COPD lung samples demonstrated increased macrophage production of IL13 and expression of MUC5AC (158373) in metaplastic mucous cells, as well as NKT markers. Kim et al. (2008) concluded that there is a transition from respiratory viral infection to chronic lung disease through persistent activation of NKT-macrophage innate immune axis.

Hwang et al. (2011) observed a significant decrease in Foxo3 (602681) expression in mice exposed to cigarette smoke. Mice lacking Foxo3 and exposed to cigarette smoke developed pulmonary emphysema and exaggerated inflammatory responses in lung, which were accompanied by downregulation of antioxidant genes. Hwang et al. (2011) concluded that FOXO3 has a significant role in the regulation of lung inflammation and in the pathogenesis of COPD and emphysema.