Recent genome-wide association studies have reported a FAM13A variant on chromosome 4q22.1 is associated with lung function and COPD. We examined this variant in a case-control study of current or former smokers with chronic obstructive pulmonary disease (COPD, n = 458), lung cancer (n = 454), or normal lung function (n = 488). Sex, age, and smoking history were comparable between groups. We confirmed the FAM13A variant (rs7671167) confers a protective effect on smoking-related COPD alone (C allele odds ratio [OR] = 0.79, P = 0.013, and CC genotype OR = 0.71, P = 0.024) and those with COPD, both with and without lung cancer (C allele OR = 0.80, P = 0.008, and CC genotype OR = 0.70, P = 0.007). The FAM13A variant also confers a protective effect on lung cancer overall (C allele OR = 0.75, P = 0.002, and CC genotype OR = 0.64, P = 0.003) even after excluding those with co-existing COPD (C allele OR = 0.67, P = 0.0007, and CC genotype OR = 0.58, P = 0.006). This was independent of age, sex, height, lung function, and smoking history. This protective effect was confined to those with nonsmall cell lung cancer (C allele OR = 0.72, P = 0.0009, and CC genotype OR = 0.61, P = 0.003). This study suggests that genetic predisposition to COPD is shared with lung cancer through shared pathogenetic factors such as the 4q22.1 locus implicating the Rho-kinase pathway.
lung cancer; chronic obstructive pulmonary disease; FAM13A; association study; polymorphism; GTPase
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).
chronic obstructive pulmonary disease; genetic association analysis; lung function; smoking; nicotine addiction
Rationale: Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood.
Objectives: To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations.
Methods: The relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN).
Measurements and Main Results: The CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10−4), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10−4 and 4.8 × 10−5), and airflow obstruction (P = 0.004 and 1.8 × 10−5) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV1. The HHIP locus was not associated with smoking intensity but was associated with FEV1/FVC (P = 1.9 × 10−4 and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function.
Conclusions: The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.
COPD exacerbations; nicotine addiction; high-resolution CT; genetic association analysis; emphysema
Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility.
Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD.
Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10−8), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated.
Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009–0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001–0.049), although these COPD associations were not replicated in two additional cohorts.
Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility.
Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).
biomarker; chronic obstructive pulmonary disease; genome-wide association study
The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10−9). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV1 (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.
Epidemiological studies indicate that tobacco smoke exposure accounts for nearly 90% of cases of chronic obstructive pulmonary disease (COPD) and lung cancer. However, genetic factors may explain why 10%–30% of smokers develop these complications. This perspective reviews the evidence suggesting that COPD is closely linked to susceptibility to lung cancer and outlines the potential relevance of this observation. Epidemiological studies show that COPD is the single most important risk factor for lung cancer among smokers and predates lung cancer in up to 80% of cases. Genome-wide association studies of lung cancer, lung function, and COPD have identified a number of overlapping “susceptibility” loci. With stringent phenotyping, it has recently been shown that several of these overlapping loci are independently associated with both COPD and lung cancer. These loci implicate genes underlying pulmonary inflammation and apoptotic processes mediated by the bronchial epithelium, and link COPD with lung cancer at a molecular genetic level. It is currently possible to derive risk models for lung cancer that incorporate lung cancer-specific genetic variants, recently identified “COPD-related” genetic variants, and clinical variables. Early studies suggest that single nucleotide polymorphism-based risk stratification of smokers might help better target novel prevention and early diagnostic strategies in lung cancer.
lung cancer; chronic obstructive pulmonary disease; association study; single nucleotide polymorphism; risk model
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.
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD), which is a heritable multi-factorial trait. Identifying the genetic determinants of COPD risk will have tremendous public health importance. This study describes the first genome-wide association study (GWAS) in COPD. We conducted a GWAS in a homogenous case-control cohort from Norway and evaluated the top 100 single nucleotide polymorphisms in the family-based International COPD Genetics Network. The polymorphisms that showed replication were further evaluated in subjects from the US National Emphysema Treatment Trial and controls from the Normative Aging Study and then in a fourth cohort of extended pedigrees from the Boston Early-Onset COPD population. Two polymorphisms in the α-nicotinic acetylcholine receptor 3/5 locus on chromosome 15 showed unambiguous evidence of association with COPD. This locus has previously been implicated in both smoking behavior and risk of lung cancer, suggesting the possibility of multiple functional polymorphisms in the region or a single polymorphism with wide phenotypic consequences. The hedgehog interacting protein (HHIP) locus on chromosome 4, which is associated with COPD, is also a significant risk locus for COPD.
Lung cancer is the leading cause of cancer death worldwide and nearly 90% of cases are attributable to smoking. Quitting smoking and early diagnosis of lung cancer, through computed tomographic screening, are the only ways to reduce mortality from lung cancer. Recent epidemiological studies show that risk prediction for lung cancer is optimized by using multivariate risk models that include age, smoking exposure, history of chronic obstructive pulmonary disease (COPD), family history of lung cancer, and body mass index. It has also been shown that COPD predates lung cancer in 65–70% of cases, conferring a four- to sixfold greater risk of lung cancer compared to smokers with normal lung function. Genome-wide association studies of smokers have identified a number of genetic variants associated with COPD or lung cancer. In a case–control study, where smokers with normal lungs were compared to smokers who had spirometry-defined COPD or histology confirmed lung cancer, several of these variants were shown to overlap, conferring the same susceptibility or protective effects on both COPD and lung cancer (independent of COPD status). In this perspective article, we show how combining clinical data with genetic variants can help identify heavy smokers at the greatest risk of lung cancer. Using this approach, we found that gene-based risk testing helped engage smokers in risk mitigating activities like quitting smoking and undertaking lung cancer screening. We suggest that such an approach could facilitate the targeted selection of smokers for cost-effective life-saving interventions.
lung cancer; COPD; risk prediction; genetic susceptibility; screening
Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP) data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs). The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS) dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5), the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD) bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus.
The pathogenesis of chronic obstructive pulmonary disease (COPD) is characterized by an interaction of environmental influences, particularly cigarette smoking, and genetic determinants. Given the global increase in COPD, research on the genomic variants that affect susceptibility to this complex disorder is reviving. In the present study, we investigated whether single nucleotide polymorphisms in 'a disinter-grin and metalloprotease' 33 (ADAM33) are associated with the development and course of COPD.
Patients and design
We genotyped 150 German COPD patients and 152 healthy controls for the presence of the F+1 and S_2 SNPs in ADAM 33 that lead to the base pair exchange G to A and C to G, respectively. To assess whether these genetic variants are influential in the course of COPD, we subdivided the cohort into two subgroups comprising 60 patients with a stable and 90 patients with an unstable course of disease.
In ADAM33, the frequency of the F+1 A allele was 35.0% among stable and 43.9% among unstable COPD subjects, which was not significantly different from the 35.5% found in the controls (P = 0.92 and P = 0.07, respectively). The frequency of the S_2 mutant allele in subjects with a stable COPD was 23.3% (P = 0.32), in subjects with an unstable course 30.6% (P = 0.47).
The study shows that there is no significant difference in the distribution of the tested SNPs between subjects with and without COPD. Furthermore, these polymorphisms appear to have no consequences for the stability of the disease course.
COPD; ADAM33; genetics
Recently, several genome-wide association studies (GWAS) have identified many susceptible single nucleotide polymorphisms (SNPs) for chronic obstructive pulmonary disease (COPD) and lung cancer which are two closely related diseases. Among those SNPs, some of them are shared by both the diseases, reflecting there is possible genetic similarity between the diseases. Here we tested the hypothesis that whether those shared SNPs are common predictor for risks or prognosis of COPD and lung cancer. Two SNPs (rs6495309 and rs1051730) located in nicotinic acetylcholine receptor alpha 3 (CHRNA3) gene were genotyped in 1511 patients with COPD, 1559 lung cancer cases and 1677 controls in southern and eastern Chinese populations. We found that the rs6495309CC and rs6495309CT/CC variant genotypes were associated with increased risks of COPD (OR = 1.32, 95% C.I. = 1.14–1.54) and lung cancer (OR = 1.57; 95% CI = 1.31–1.87), respectively. The rs6495309CC genotype contributed to more rapid decline of annual Forced expiratory volume in one second (FEV1) in both COPD cases and controls (P<0.05), and it was associated with advanced stages of COPD (P = 0.033); the rs6495309CT/CC genotypes conferred a poor survival for lung cancer (HR = 1.41, 95%CI = 1.13–1.75). The luciferase assays further showed that nicotine and other tobacco chemicals had diverse effects on the luciferase activity of the rs6495309C or T alleles. However, none of these effects were found for another SNP, rs1051730G>A. The data show a statistical association and suggest biological plausibility that the rs6495309T>C polymorphism contributed to increased risks and poor prognosis of both COPD and lung cancer.
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide. Recent genome-wide association studies (GWAS) have identified robust susceptibility loci associated with COPD. However, the mechanisms mediating the risk conferred by these loci remain to be found. The goal of this study was to identify causal genes/variants within susceptibility loci associated with COPD. In the discovery cohort, genome-wide gene expression profiles of 500 non-tumor lung specimens were obtained from patients undergoing lung surgery. Blood-DNA from the same patients were genotyped for 1,2 million SNPs. Following genotyping and gene expression quality control filters, 409 samples were analyzed. Lung expression quantitative trait loci (eQTLs) were identified and overlaid onto three COPD susceptibility loci derived from GWAS; 4q31 (HHIP), 4q22 (FAM13A), and 19q13 (RAB4B, EGLN2, MIA, CYP2A6). Significant eQTLs were replicated in two independent datasets (n = 363 and 339). SNPs previously associated with COPD and lung function on 4q31 (rs1828591, rs13118928) were associated with the mRNA expression of HHIP. An association between mRNA expression level of FAM13A and SNP rs2045517 was detected at 4q22, but did not reach statistical significance. At 19q13, significant eQTLs were detected with EGLN2. In summary, this study supports HHIP, FAM13A, and EGLN2 as the most likely causal COPD genes on 4q31, 4q22, and 19q13, respectively. Strong lung eQTL SNPs identified in this study will need to be tested for association with COPD in case-control studies. Further functional studies will also be needed to understand the role of genes regulated by disease-related variants in COPD.
Environmental exposures and genetic susceptibility can contribute to lung function decline in chronic obstructive pulmonary disease (COPD). The environmental factors are better known than the genetic factors. One of the commonest reasons of accelerated forced expiratory volume in one second (FEV1) decline in COPD is the continuation of the smoking habit. In addition, COPD patients have frequent acute respiratory infections which can also accelerate the decline of FEV1. All of the gene variants that have been reported in association with accelerated decline of lung function in COPD represent advancement because the findings generate plausible hypotheses about the possible mechanisms by which gene products could accelerate or avert FEV1 decline. Unfortunately, the results have not been consistently replicated and, animal models required to functionally assess the genetic findings, have not yet yielded sufficient data. Genome-wide association studies should provide more definitive results in COPD and other multigenic conditions. Until these studies are reported, the data to date suggest that products encoded by the alpha-1 antitrypsin, some matrix metalloproteinases, and a number of antioxidant genes are associated with accelerated FEV1 decline in COPD. Data on gene variants associated with acute exacerbations of COPD are now emerging.
lung function; COPD; Smoking; genes
Adiponectin is reported to be related to the development of chronic obstructive pulmonary disease (COPD). Genetic variants in the gene encoding adiponectin (ADIPOQ) have been reported to be associated with adiponectin level in several genome–wide linkage and association studies. However, relatively little is known about the effects of ADIPOQ gene variants on COPD susceptibility. We determined the frequencies of single-nucleotide polymorphisms (SNPs) in ADIPOQ in a Chinese Han population and their possible association with COPD susceptibility.
We conducted a case–control study of 279 COPD patients and 367 age- and gender-distribution-matched control subjects. Seven tagging SNPs in ADIPOQ, including rs710445, rs16861205, rs822396, rs7627128, rs1501299, rs3821799 and rs1063537 were genotyped by SNaPshot. Association analysis of genotypes/alleles and haplotypes constructed from these loci with COPD was conducted under different genetic models.
The alleles or genotypes of rs1501299 distributed significantly differently in COPD patients and controls (allele: P = 0.002, OR = 1.43 and 95%CI = 1.14–1.79; genotype: P = 0.008). The allele A at rs1501299 was potentially associated with an increased risk of COPD in all dominant model analysis (P = 0.009; OR: 1.54; 95%CI: 1.11–2.13), recessive model analyses (P = 0.015; OR: 1.75; 95% CI: 1.11–2.75) and additive model analyses (P = 0.003; OR: 2.11; 95% CI: 1.29–3.47). In haplotype analysis, we observed haplotypes AAAAACT and GGACCTC had protective effects, while haplotypes AGAACTC, AGGCCTC, GGAACTC, GGACACT and GGGCCTC were significantly associated with the increased risk of COPD.
We conducted the first investigation of the association between the SNPs in ADIPOQ and COPD risk. Our current findings suggest that ADIPOQ may be a potential risk gene for COPD. Further studies in larger groups are warranted to confirm our results.
Common genetic variation may play an important role in altering chronic obstructive pulmonary disease (COPD) risk. In Xuanwei, China, the COPD rate is more than twice the Chinese national average, and COPD is strongly associated with in-home coal use. To identify genetic variation that may be associated with COPD in a population with substantial in-home coal smoke exposures, we evaluated 1,261 single nucleotide polymorphisms (SNPs) in 380 candidate genes potentially relevant for cancer and other human diseases in a population-based case-control study in Xuanwei (53 cases; 107 controls). PTEN was the most significantly associated gene with COPD in a minP analysis using 20,000 permutations (P = 0.00005). SNP-based analyses found that homozygote variant carriers of PTEN rs701848 (ORTT = 0.12, 95%CI = 0.03 - 0.47) had a significant decreased risk of COPD. PTEN, or phosphatase and tensin homolog, is an important regulator of cell cycle progression and cellular survival via the AKT signaling pathway. Our exploratory analysis suggests that genetic variation in PTEN may be an important risk factor of COPD in Xuanwei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuanwei and other populations with coal smoke exposures.
COPD; cell cycle; apoptosis; AKT; PTEN
Epidemiological studies show that approximately 20–30% of chronic smokers develop chronic obstructive pulmonary disease (COPD) while 10–15% develop lung cancer. COPD pre-exists lung cancer in 50–90% of cases and has a heritability of 40–77%, much greater than for lung cancer with heritability of 15–25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400) subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV1, appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV1 is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the “risk genotypes” derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70). We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer.
Cachexia, whether assessed by body mass index (BMI) or fat-free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD), and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among patients with COPD suggests a role for genetic susceptibility. The objective of the present study was to determine genetic susceptibility loci involved in the development of low BMI and FFMI in subjects with COPD. A genome-wide association study (GWAS) of BMI was conducted in three independent cohorts of European descent with Global Initiative for Chronic Obstructive Lung Disease stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE; n = 1,734); Norway-Bergen cohort (n = 851); and a subset of subjects from the National Emphysema Treatment Trial (NETT; n = 365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity–associated (FTO) gene, and BMI (P = 4.97 × 10−7) and FFMI (P = 1.19 × 10−7). We replicated the association in a fourth, independent cohort consisting of 502 subjects with COPD from COPDGene (P = 6 × 10−3). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume at 1 second, varied significantly by FTO genotype. Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD.
chronic obstructive pulmonary disease genetics; chronic obstructive pulmonary disease epidemiology; chronic obstructive pulmonary disease metabolism; genome-wide association study
On-going airway inflammation is characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the key factors determining the decrease in lung function, an important clinical parameter of COPD, are not clear. Genome-wide linkage analyses provide evidence for significant linkage to airway obstruction susceptibility loci on chromosome 8p23, the location of the human defensin gene cluster. Moreover, a genetic variation in the defensin beta 1 (DEFB1) gene was found to be associated with COPD. Therefore, we hypothesized that DEFB1 is differently regulated and expressed in human lungs during COPD progression. Gene expression of DEFB1 was assessed in bronchial epithelium and BAL fluid cells of healthy controls and patients with COPD and using bisulfite sequencing and ChIP analysis, the epigenetic control of DEFB1 mRNA expression was investigated. We can demonstrate that DEFB1 mRNA expression was significantly increased in bronchopulmonary specimen of patients with COPD (n = 34) vs. healthy controls (n = 10) (p<0.0001). Furthermore, a significant correlation could be detected between DEFB1 and functional parameters such as FEV1 (p = 0.0024) and the FEV1/VC ratio (p = 0.0005). Upregulation of DEFB1 mRNA was paralleled by changes in HDAC1-3, HDAC5 and HDAC8 mRNA expression. Whereas bisulfite sequencing revealed no differences in the methylation state of DEFB1 promoter between patients with COPD and controls, ChIP analysis showed that enhanced DEFB1 mRNA expression was associated with the establishment of an active histone code. Thus, expression of human DEFB1 is upregulated and related to the decrease in pulmonary function in patients with COPD.
Similar to other common chronic diseases, chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder with multiple disease subtypes. Candidate gene studies have found genetic associations for COPD-related phenotypes that may be relevant for pharmacogenetics studies, including lung function decline and COPD exacerbations. However, few COPD pharmacogenetics studies have been completed. Most studies have focused on the role of variants in the β2-adrenergic receptor gene on bronchodilator response, but the findings have been inconclusive. Candidate gene studies highlight the concept that genes for COPD susceptibility may also be relevant in COPD pharmacogenetics. Currently, there are no clinical applications of pharmacogenetics to COPD therapy, but the use of pharmacogenetics to determine initial smoking cessation therapy may be closer to clinical application.
bronchodilator response; chronic obstructive pulmonary disease; emphysema; exacerbation; pharmacogenetics; smoking cessation; SNP
Genetic variation in nicotinic acetylcholine receptor subunit genes (nAChRs) is associated with lung function level and chronic obstructive pulmonary disease (COPD). It is unknown whether these variants also predispose to an accelerated lung function decline. We investigated the association of nAChR susceptibility variants with lung function decline and COPD severity. The rs1051730 and rs8034191 variants were genotyped in a population-based cohort of 1,226 heavy smokers (COPACETIC) and in an independent cohort of 883 heavy smokers, of which 653 with COPD of varying severity (LEUVEN). Participants underwent pulmonary function tests at baseline. Lung function decline was assessed over a median follow-up of 3 years in COPACETIC. Current smokers homozygous for the rs1051730 A-allele or rs8034191 G-allele had significantly greater FEV1/FVC decline than homozygous carriers of wild-type alleles (3.3% and 4.3%, p = 0.026 and p = 0.009, respectively). In the LEUVEN cohort, rs1051730 AA-carriers and rs8034191 GG-carriers had a two-fold increased risk to suffer from COPD GOLD IV (OR 2.29, 95% confidence interval [CI] = 1.11–4.75; p = 0.025 and OR = 2.42, 95% [CI] = 1.18–4.95; p = 0.016, respectively). The same risk alleles conferred, respectively, a five- and four-fold increased risk to be referred for lung transplantation because of end-stage COPD (OR = 5.0, 95% [CI] = 1.68–14.89; p = 0.004 and OR = 4.06, 95% [CI] = 1.39–11.88; p = 0.010). In Europeans, variants in nAChRs associate with an accelerated lung function decline in current smokers and with clinically relevant COPD.
The identification of gene-by-environment interactions is important to understand the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and FEV1; however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity.
We examined the relationship between FEV1 and pack-years of smoking exposure in 4 large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, we compared the accuracy and power of two different approaches to model smoking by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects.
We identified nonlinear relationships between smoking and FEV1 in 4 large cohorts. We demonstrated that in most situations where the relationship between pack-years and FEV1 is nonlinear, a piecewise-linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. We applied the piecewise linear approach to a genetic association analysis of the PI*Z allele in the Norway case-control cohort and identified a potential PI*Z-by-smoking interaction (p=0.03 for FEV1 analysis, p= 0.01 for COPD susceptibility analysis).
In study samples with subjects having a wide range of COPD severity, a nonlinear relationship between pack-years of smoking and FEV1 is likely. In this setting, approaches that account for this nonlinearity can be more powerful and less-biased than the commonly-used approach of using total pack-years to model the smoking effect.
smoking; FEV1; gene-by-environment interaction; COPD; gene
Chronic obstructive pulmonary disease (COPD) is predominantly the consequence of chronic smoking exposure, but its development may be influenced by genetic variants that affect lung remodelling, inflammation, and defence from oxidant stress. A study was undertaken to determine whether genetic variants within genes encoding the antioxidant enzymes superoxide dismutase (SOD) and catalase may be associated with the development of impaired lung function.
In a case‐control study, the allele and genotype frequencies of functional polymorphisms from SOD1 (CuZnSOD), SOD2 (MnSOD), SOD3 (extracellular SOD), and catalase (CAT) were compared in chronic smokers with normal lung function (resistant smokers) and in those with COPD.
Significantly higher frequencies of the G allele and CG/GG genotype of the 213 SOD3 polymorphism were found in resistant smokers (odds ratios (ORs) 4.3 (95% CI 1.5 to 13.3) and 4.2, 95% CI 1.4 to 13.3), Bonferroni corrected p = 0.02 and p = 0.02, respectively) than in those with COPD. There were no differences between the COPD and resistant smokers for the SOD1, SOD2, or CAT polymorphisms tested.
The 213Gly variant of the SOD3 gene may, through antioxidant or anti‐inflammatory effects, confer a degree of resistance in some smokers to the development of COPD.
antioxidant; chronic obstructive pulmonary disease; genes; smokers; lung function
Chronic Obstructive Pulmonary Disease (COPD) is a strong risk factor for lung cancer. Published studies regarding variations of genes encoding glutathione metabolism, DNA repair, and inflammatory response pathways in susceptibility to COPD were inconclusive.
We evaluated 470 single nucleotide polymorphisms (SNPs) from 56 genes of these 3 pathways in 620 cases and 893 controls to identify susceptibility markers for COPD risk, using existing resources. We assessed SNP- and gene-level effects adjusting for sex, age, and smoking status. Differential genetic effects on disease risk with and without lung cancer were also assessed; cumulative risk models were established.
Twenty-one SNPs were found to be significantly associated with risk of COPD (P<0.01); gene-based analyses confirmed 2 genes (GCLC and GSS) and identified 3 additional (GSTO2, ERCC1, and RRM1). Carrying 12 high-risk alleles may increase risk by 2.7-fold; 8 SNPs altered COPD risk with lung cancer 3.1-fold, and 4 SNPs altered the risk without lung cancer 2.3-fold.
Our findings indicate that multiple genetic variations in the 3 selected pathways contribute to COPD risk through GCLC, GSS, GSTO2, ERCC1, and RRM1 genes. Functional studies are needed to elucidate the mechanisms of these genes in the development of COPD, lung cancer, or both.
Chronic Obstructive Pulmonary Disease; Glutathione Metabolism Pathway; DNA Repair Pathway; Inflammatory Response Pathway
Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death. The most common cause of COPD is smoking. There is evidence suggesting that genetic factors influence COPD susceptibility and variants in several candidate genes have been significantly associated with COPD. In this study, we aimed to investigate the possible association of the TNF-α –308, SPB+1580, IL-13 –1055 gene polymorphisms and latent adenovirus C infection with COPD in an Egyptian population.
Material and methods
Our study included 115 subjects (75 smokers with COPD, 25 resistant smokers and 15 non-smokers) who were subjected to spirometric measurements, identification of adenovirus C and genotyping of TNF-α –308G/A, SP-B+1580 C/T and IL-13 –1055 C/T polymorphisms by real-time PCR.
The adenovirus C gene was identified in all subjects. The distribution of TNF-α genotypes showed no significant differences between different groups. However, homozygous A genotype was associated with a significant decrease in FEV1, FEV1/FVC and FEF25/75% of predicted in COPD (p < 0.05). As regards SP-B genotypes, resistant smokers had a significantly higher homozygous T genotype frequency compared to COPD and non smokers (p = 0.005). Interleukin 13 genotypes showed no significant difference between different groups. There was a significant decrease in FEF25/75% of predicted in T allele carriers in COPD patients (p = 0.001).
The COPD is a disease caused by the interaction of combined genes and environmental influences, in the presence of smoking and latent adenovirus C infection, TNF-α –308A, SPB +1580 T and IL-13 –1055 T polymorphisms predispose to the development of COPD.
single nucleotide polymorphism; smoking; adenovirus C; chronic obstructive pulmonary disease