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1.  SOX5 Is a Candidate Gene for Chronic Obstructive Pulmonary Disease Susceptibility and Is Necessary for Lung Development 
Rationale: Chromosome 12p has been linked to chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD Study (BEOCOPD), but a susceptibility gene in that region has not been identified.
Objectives: We used high-density single-nucleotide polymorphism (SNP) mapping to implicate a COPD susceptibility gene and an animal model to determine the potential role of SOX5 in lung development and COPD.
Methods: On chromosome 12p, we genotyped 1,387 SNPs in 386 COPD cases from the National Emphysema Treatment Trial and 424 control smokers from the Normative Aging Study. SNPs with significant associations were then tested in the BEOCOPD study and the International COPD Genetics Network. Based on the human results, we assessed histology and gene expression in the lungs of Sox5−/− mice.
Measurements and Main Results: In the case-control analysis, 27 SNPs were significant at P ≤ 0.01. The most significant SNP in the BEOCOPD replication was rs11046966 (National Emphysema Treatment Trial–Normative Aging Study P = 6.0 × 10−4, BEOCOPD P = 1.5 × 10−5, combined P = 1.7 × 10−7), located 3′ to the gene SOX5. Association with rs11046966 was not replicated in the International COPD Genetics Network. Sox5−/− mice showed abnormal lung development, with a delay in maturation before the saccular stage, as early as E16.5. Lung pathology in Sox5−/− lungs was associated with a decrease in fibronectin expression, an extracellular matrix component critical for branching morphogenesis.
Conclusions: Genetic variation in the transcription factor SOX5 is associated with COPD susceptibility. A mouse model suggests that the effect may be due, in part, to its effects on lung development and/or repair processes.
PMCID: PMC3137139  PMID: 21330457
chronic obstructive pulmonary disease; emphysema; knockout mice; lung development; single nucleotide polymorphism
2.  A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci 
PLoS Genetics  2009;5(3):e1000421.
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.
Author Summary
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.
PMCID: PMC2650282  PMID: 19300482
3.  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).
PMCID: PMC3423462  PMID: 22461431
chronic obstructive pulmonary disease; genetic association analysis; lung function; smoking; nicotine addiction
4.  PLAUR polymorphisms and lung function in UK smokers 
BMC Medical Genetics  2009;10:112.
We have previously identified Urokinase Plasminogen Activator Receptor (PLAUR) as an asthma susceptibility gene. In the current study we tested the hypothesis that PLAUR single nucleotide polymorphisms (SNPs) determine baseline lung function and contribute to the development of Chronic Obstructive Pulmonary Disease (COPD) in smokers.
25 PLAUR SNPs were genotyped in COPD subjects and individuals with smoking history (n = 992). Linear regression was used to determine the effects of polymorphism on baseline lung function (FEV1, FEV1/FVC) in all smokers. Genotype frequencies were compared in spirometry defined smoking controls (n = 176) versus COPD cases (n = 599) and COPD severity (GOLD stratification) using logistic regression.
Five SNPs showed a significant association (p < 0.01) with baseline lung function; rs2302524(Lys220Arg) and rs2283628(intron 3) were associated with lower and higher FEV1 respectively. rs740587(-22346), rs11668247(-20040) and rs344779(-3666) in the 5'region were associated with increased FEV1/FVC ratio. rs740587 was also protective for COPD susceptibility and rs11668247 was protective for COPD severity although no allele dose relationship was apparent. Interestingly, several of these associations were driven by male smokers not females.
This study provides tentative evidence that the asthma associated gene PLAUR also influences baseline lung function in smokers. However the case-control analyses do not support the conclusion that PLAUR is a major COPD susceptibility gene in smokers. PLAUR is a key serine protease receptor involved in the generation of plasmin and has been implicated in airway remodelling.
PMCID: PMC2784766  PMID: 19878584
5.  Involvement of surfactant protein D in emphysema revealed by genetic association study 
Surfactant protein D (SFTPD) induces emphysema in knockout mice, but the association of SFTPD with chronic obstructive pulmonary disease (COPD) and emphysema in humans is unclear. Therefore, we aimed to determine the association between genetic variations in SFTPD and susceptibility to COPD and emphysema.
Two populations were studied: population A comprised 270 smokers, including 188 COPD and 82 at-risk subjects, and population B comprised 1131 autopsy cases including 160 cases with emphysema. Six single-nucleotide polymorphisms (SNPs) that tagged the linkage disequilibrium blocks on the entire SFTPD gene were genotyped; the associations of the genotypes with COPD, pulmonary function, percentage of the low-attenuation area (LAA%), and percentage of the airway wall area (WA%) were determined in population A. In population B, the associations of the genotypes with emphysema were assessed.
A C allele at SNP rs721917 that results in the replacement of Met with Thr at position 11 in SFTPD was positively correlated with the LAA% in the upper lung (P=1.1 × 10−5) and overall LAA% (P=1.0 × 10−4), and negatively correlated with the serum concentration of SFTPD (P=7 × 10−11) in the population A. The C/C (rs721917/rs10887199) haplotype was associated with emphysema in both the populations.
Subjects with a C allele at rs721917 have a lower serum SFTPD concentration and are more susceptible to emphysema. This suggests a protective effect of SFTPD against COPD and emphysema.
PMCID: PMC3260918  PMID: 21934714
chronic obstructive pulmonary disease; emphysema; genetic variation; pulmonary surfactant-associated protein D
6.  Association of TNF-α –308G/A, SP-B 1580 C/T, IL-13 –1055 C/T gene polymorphisms and latent adenoviral infection with chronic obstructive pulmonary disease in an Egyptian population 
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.
PMCID: PMC3361041  PMID: 22662002
single nucleotide polymorphism; smoking; adenovirus C; chronic obstructive pulmonary disease
7.  Association of MMP - 12 polymorphisms with severe and very severe COPD: A case control study of MMPs - 1, 9 and 12 in a European population 
BMC Medical Genetics  2010;11:7.
Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease - antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies.
To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history.
Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV.
Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.
PMCID: PMC2820470  PMID: 20078883
8.  Polymorphisms for microsomal epoxide hydrolase and genetic susceptibility to COPD 
Although smoking is the major causal factor in the development of chronic obstructive pulmonary disease (COPD), only 10–20% of chronic heavy cigarette smokers develop symptomatic COPD, which suggests the presence of genetic susceptibility. The human microsomal epoxide hydrolase (EH) is a metabolizing enzyme which involves the process of numerous reactive epoxide intermediates and contains polymorphic alleles which are associated with altered EH activity and may be linked to increased risk for COPD. To determine whether the EH polymorphisms contributed to increased risk for COPD, prevalence of the EH codons 113 and 139 polymorphisms were compared between COPD patients and controls using a PCR-RFLP analysis using genomic DNA isolated from 131 COPD patients and 262 individually matched controls by age (± 5 years) among Caucasians with 1:2 ratio. Significantly increased risk for COPD was observed for subjects with the EH113His/His genotypes (OR =2.4, 95% CI=1.1–5.1). These results were consistent with the fact that a significant trend towards increased risk was observed with predicted less protective EH codon 113 genotypes (p = 0.03, trend test). A similar association was not observed for EH codon139 polymorphism. As expected, a significant correlation between smoking dose and severity of COPD was observed (p<0.001). These results suggest that EH codon 113 polymorphism may modify risk for COPD.
PMCID: PMC3705731  PMID: 15702235
chronic obstructive pulmonary disease; epoxide hydrolase; genetic polymorphism; genetic susceptibility
9.  SERPINE2 Polymorphisms and Chronic Obstructive Pulmonary Disease 
Journal of Korean Medical Science  2009;24(6):1119-1125.
A number of genome-wide linkage analyses have identified the 2q33.3-2q37.2 region as most likely to contain the genes that contribute to the susceptibility to chronic obstructive pulmonary disease (COPD). It was hypothesized that the SERPINE2 gene, which is one of the genes located at the 2q33.3-2q37.2 region, may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, the association of four SERPINE2 single nucleotide polymorphisms (SNPs; rs16865421A>G, rs7583463A>C, rs729631C>G, and rs6734100C>G) with the risk of COPD was investigated in a case-control study of 311 COPD patients and 386 controls. The SNP rs16865421 was associated with a significantly decreased risk of COPD in a dominant model for the polymorphic allele (adjusted odds ratio [OR]=0.66, 95% confidence interval [CI]=0.45-0.97, P=0.03). In haplotype analysis, the GACC haplotype carrying the polymorphic allele at the rs16865421 was associated with a significantly decreased risk of COPD when compared to the AACC haplotype (adjusted OR=0.58, 95% CI=0.38-0.89, P=0.01), and this effect was evident in younger individuals (adjusted OR=0.30, 95% CI=0.14-0.64, P=0.002). This study suggests that the SERPINE2 gene contributes to the susceptibility to COPD.
PMCID: PMC2775861  PMID: 19949669
Serpine2; Polymorphism; Pulmonary Disease, Chronic Obstructive
10.  The Relationship between Dietary Fatty Acids and Inflammatory Genes on the Obese Phenotype and Serum Lipids 
Nutrients  2013;5(5):1672-1705.
Obesity, a chronic low-grade inflammatory condition is associated with the development of many comorbidities including dyslipidemia. This review examines interactions between single nucleotide polymorphisms (SNP) in the inflammatory genes tumor necrosis alpha (TNFA) and interleukin-6 (IL-6) and dietary fatty acids, and their relationship with obesity and serum lipid levels. In summary, dietary fatty acids, in particular saturated fatty acids and the omega-3 and omega-6 polyunsaturated fatty acids, impact the expression of the cytokine genes TNFA and IL-6, and alter TNFα and IL-6 production. In addition, sequence variants in these genes have also been shown to alter their gene expression and plasma levels, and are associated with obesity, measures of adiposity and serum lipid concentrations. When interactions between dietary fatty acids and TNFA and IL-6 SNPs on obesity and serum lipid were analyzed, both the quantity and quality of dietary fatty acids modulated the relationship between TNFA and IL-6 SNPs on obesity and serum lipid profiles, thereby impacting the association between phenotype and genotype. Researching these diet–gene interactions more extensively, and understanding the role of ethnicity as a confounder in these relationships, may contribute to a better understanding of the inter-individual variability in the obese phenotype.
PMCID: PMC3708344  PMID: 23698162
adipose tissue; dyslipidemia; SNP; dietary fat; inflammation; ethnicity
11.  Polymorphisms in Surfactant Protein–D Are Associated with Chronic Obstructive Pulmonary Disease 
Chronic obstructive pulmonary disease (COPD) is characterized by alveolar destruction and abnormal inflammatory responses to noxious stimuli. Surfactant protein–D (SFTPD) is immunomodulatory and essential to host defense. We hypothesized that polymorphisms in SFTPD could influence the susceptibility to COPD. We genotyped six single-nucleotide polymorphisms (SNPs) in surfactant protein D in 389 patients with COPD in the National Emphysema Treatment Trial (NETT) and 472 smoking control subjects from the Normative Aging Study (NAS). Case-control association analysis was performed using Cochran–Armitage trend tests and multivariate logistic regression. The replication of significant associations was attempted in the Boston Early-Onset COPD Study, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and the Bergen Cohort. We also correlated SFTPD genotypes with serum concentrations of surfactant protein–D (SP-D) in the ECLIPSE Study. In the NETT–NAS case-control analysis, four SFTPD SNPs were associated with susceptibility to COPD: rs2245121 (P = 0.01), rs911887 (P = 0.006), rs6413520 (P = 0.004), and rs721917 (P = 0.006). In the family-based analysis of the Boston Early-Onset COPD Study, rs911887 was associated with prebronchodilator and postbronchodilator FEV1 (P = 0.003 and P = 0.02, respectively). An intronic SNP in SFTPD, rs7078012, was associated with COPD in the ECLIPSE Study and the Bergen Cohort. Multiple SFTPD SNPs were associated with serum SP-D concentrations in the ECLIPSE Study. We demonstrated an association of polymorphisms in SFTPD with COPD in multiple populations. We demonstrated a correlation between SFTPD SNPs and SP-D protein concentrations. The SNPs associated with COPD and SP-D concentrations differed, suggesting distinct genetic influences on susceptibility to COPD and SP-D concentrations.
PMCID: PMC3095932  PMID: 20448057
COPD; surfactant protein–D; single-nucleotide polymorphisms; genetics
12.  A disintegrin and metalloprotease 33 and chronic obstructive pulmonary disease pathophysiology 
Thorax  2006;62(3):242-247.
Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with increasing prevalence and mortality. It is associated with airway obstruction, increased airway hyper‐responsiveness (AHR), and ongoing airway and lung inflammation dominated by CD8 lymphocytes and neutrophils. Single‐nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene have been associated with AHR and COPD.
To assess whether SNPs in ADAM33 are associated with the severity of AHR and airway inflammation in COPD.
Eight SNPs in ADAM33 (F+1, Q‐1, S_1, S_2, ST+5, T_1, T_2, V_4) were genotyped in 111 patients with COPD (96 males, 69 current smokers, mean (standard deviation (SD)), aged 62 (8) years, median pack‐years 42 (IQR 31–55), mean postbronchodilator forced expiratory volume in 1 s (FEV1)% predicted 63 (9). Provocative concentration of methacholine causing a decrease in FEV1 of 20% (PC20 methacholine), sputum and bronchial biopsies were collected.
Patients with the ST+5 AA genotype had more severe AHR, higher numbers of sputum inflammatory cells and CD8 cells in bronchial biopsies than patients with the GG genotype (p = 0.03, 0.05 and 0.01, respectively). CD8 cell numbers were lower in patients carrying the minor allele of SNP T_1 and T_2, and homozygotic minor variants of SNP S_2 compared with the wild type (p = 0.02, 0.01 and 0.02, respectively).
This is the first study revealing that SNPs in a gene that confers susceptibility to COPD in the general population—that is, ADAM33—are associated with AHR and airway inflammation in COPD. These findings constitute an important step forward in linking gene polymorphisms with COPD pathophysiology, thereby possibly contributing to better treatments for this progressive and disabling disease in the future.
PMCID: PMC2117167  PMID: 17090574
13.  Genetic Variants Associated with the Risk of Chronic Obstructive Pulmonary Disease with and without Lung Cancer 
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.
PMCID: PMC3414259  PMID: 22044695
Chronic Obstructive Pulmonary Disease; Glutathione Metabolism Pathway; DNA Repair Pathway; Inflammatory Response Pathway
COPD  2010;7(4):262-268.
Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes.
We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1) and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n=389) and smoking controls from the Normative Aging Study (NAS, n=472). We examined whether the SNPs were associated with COPD status, lung function variables, and quantitative CT measurements of emphysema and airway wall thickness. Further, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n=3061) and the Boston Early-Onset COPD Study (EOCOPD, n=949).
In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p=0.029 and p=0.0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p=0.048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations.
In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.
PMCID: PMC2923920  PMID: 20673035
15.  Nicotinic acetylcholine receptor variants associated with susceptibility to chronic obstructive pulmonary disease: a meta-analysis 
Respiratory Research  2011;12(1):158.
Only 10-15% of smokers develop chronic obstructive pulmonary disease (COPD) which indicates genetic susceptibility to the disease. Recent studies suggested an association between COPD and polymorphisms in CHRNA coding subunits of nicotinic acetylcholine receptor. Herein, we performed a meta-analysis to clarify the impact of CHRNA variants on COPD.
We searched Web of Knowledge and Medline from 1990 through June 2011 for COPD gene studies reporting variants on CHRNA. Pooled odds ratios (ORs) were calculated using the major allele or genotype as reference group.
Among seven reported variants in CHRNA, rs1051730 was finally analyzed with sufficient studies. Totally 3460 COPD and 11437 controls from 7 individual studies were pooled-analyzed. A-allele of rs1051730 was associated with an increased risk of COPD regardless of smoking exposure (pooled OR = 1.26, 95% CI 1.18-1.34, p < 10-5). At the genotypic level, the ORs gradually increased per A-allele (OR = 1.27 and 1.50 for GA and AA respectively, p < 10-5). Besides, AA genotype exhibited an association with reduced FEV1% predicted (mean difference 3.51%, 95%CI 0.87-6.16%, p = 0.009) and increased risk of emphysema (OR 1.93, 95%CI 1.29-2.90, p = 0.001).
Our findings suggest that rs1051730 in CHRNA is a susceptibility variant for COPD, in terms of both airway obstruction and parenchyma destruction.
PMCID: PMC3283485  PMID: 22176972
Chronic Obstructive Pulmonary Disease (COPD); Nicotine acetylcholine receptor (nAChR); CHRNA -; ; Single nucleotide polymorphism (SNP)
16.  A Functional Polymorphism in the CHRNA3 Gene and Risk of Chronic Obstructive Pulmonary Disease in a Korean Population 
Journal of Korean Medical Science  2012;27(12):1536-1540.
A genome-wide association study has identified the 15q25 region as being associated with the risk of chronic obstructive pulmonary disease (COPD) in Caucasians. This study intended as a confirmatory assessment of this association in a Korean population. The rs6495309C > T polymorphism in the promoter of nicotinic acetylcholine receptor alpha subunit 3 (CHRNA3) gene was investigated in a case-control study that consisted of 406 patients with COPD and 394 healthy control subjects. The rs6495309 CT or TT genotype was associated with a significantly decreased risk of COPD when compared to the rs6495309 CC genotype (adjusted odds ratio = 0.69, 95% confidence interval = 0.50-0.95, P = 0.023). The effect of the rs6495309C > T on the risk of COPD was more evident in moderate to very severe COPD than in mild COPD under a dominant model for the variant T allele (P = 0.024 for homogeneity). The CHRNA3 rs6495309C > T polymorphism on chromosome 15q25 is associated with the risk of COPD in a Korean population.
PMCID: PMC3524434  PMID: 23255854
CHRNA3; Pulmonary Disease, Chronic Obstructive; Polymorphism
17.  Genetic Variations in ADIPOQ Gene Are Associated with Chronic Obstructive Pulmonary Disease 
PLoS ONE  2012;7(11):e50848.
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.
PMCID: PMC3508992  PMID: 23209832
18.  CTLA-4 gene polymorphisms and susceptibility to chronic obstructive pulmonary disease 
Objective: The aim of this study was to investigate whether four single nucleotide polymorphisms (SNPs) in CTLA-4 gene are associated with chronic obstructive pulmonary disease (COPD) in a Chinese population. Methods: Samples were collected from a Chinese population and analyzed for the association of SNPs in CTLA-4 gene with COPD in a case-control study. Four SNPs (rs231775, rs3087243, rs231725, rs5742909) in CTLA-4 gene were chosen and genotyped. The results were then analyzed using statistical methods. Results: We found that none of these four SNPs (rs231775, rs3087243, rs231725, rs5742909) in CTLA-4 gene were associated with the disease. Conclusion: Our data suggested that there was no significant association between these four SNPs in CTLA-4 gene and COPD susceptibility in a Chinese population.
PMCID: PMC3816826  PMID: 24228119
CTLA-4; chronic obstructive pulmonary disease; polymorphisms
19.  Effect of heme oxygenase-1 polymorphisms on lung function and gene expression 
BMC Medical Genetics  2011;12:117.
Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects.
We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated.
We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages.
We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.
PMCID: PMC3180266  PMID: 21902835
Heme oxygenase; polymorphism; chronic obstructive pulmonary disease
20.  Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease 
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 (NCT 00292552).
PMCID: PMC3622441  PMID: 23144326
biomarker; chronic obstructive pulmonary disease; genome-wide association study
21.  Association of genetic polymorphisms with chronic obstructive pulmonary disease in the Chinese Han population: a case–control study 
BMC Medical Genomics  2012;5:64.
Chronic obstructive pulmonary disease (COPD) is influenced by both environmental and genetic factors. Few gene studies of the Chinese population have focused on COPD. We investigated candidate genes associated with susceptibility to COPD in the Chinese Han population.
A total of 331 COPD patients and 213 control subjects were recruited for this study. Nighty-seven single-nucleotide polymorphisms (SNPs) of 46 genes were selected for genotyping. Genotypes were determined using multiplex polymerase chain reaction (PCR).
Significant differences between patients and healthy controls were observed in the allele frequencies of seven SNPs: rs1205 C, rs2353397 C, rs20541 T, rs2070600 G, rs10947233 G, rs1800629 G, and rs2241712 A. After Bonferroni correction, rs2353397 C was most strongly associated with susceptibility to COPD. Haplotype analysis showed that the frequencies of the GC, GT haplotypes of rs2241718 (TGF-β1 gene), and rs6957 (CDC97 gene) were significantly higher in the control group than in the COPD case group (p=1.88×10-9); the frequencies of the TT haplotype of rs1205 and rs2808630 (CRP gene) were significantly higher in the control group (p=0.0377).
Our study suggests some genetic variants associated with the susceptibility of COPD in the Chinese Han population.
PMCID: PMC3582579  PMID: 23267696
COPD; Single-nucleotide polymorphisms; Genotype; Allele frequencies
22.  Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease 
PLoS ONE  2011;6(9):e24395.
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.
PMCID: PMC3174957  PMID: 21949713
23.  Genetic Polymorphism of Matrix Metalloproteinase Family and Chronic Obstructive Pulmonary Disease Susceptibility: a Meta-analysis 
Scientific Reports  2013;3:2818.
Matrix metalloproteinase (MMP) family is considered to be associated with chronic obstructive pulmonary disease (COPD) pathogenesis, however, no consistent results have been provided by previous studies. In this report, we performed Meta analysis to investigate the association between four kinds of MMP single nucleotide polymorphisms (SNP, MMP1 -1607 1G/2G, MMP3 -1171 5A/6A, MMP9 -1562 C/T, MMP12 -82 A/G) and COPD risk from 21 studies including 4184 cases and 5716 controls. Both overall and subgroup association between SNP and COPD susceptibility were tested. There was no evident association between MMP polymorphisms and COPD susceptibility in general population. On the other hand, subgroup analysis suggested that MMP9 -1562 C/T polymorphism was related to COPD, as we found that C allele carriers were at lower risk in some subgroups stratified by lung function, age and genotype identification method, compared with TT homozygotes. Our results indicated the genotype TT might be one genetic risk factor of severe COPD.
PMCID: PMC3788362  PMID: 24085258
24.  Genetic Associations With Hypoxemia and Pulmonary Arterial Pressure in COPD* 
Chest  2008;135(3):737-744.
Hypoxemia, hypercarbia, and pulmonary arterial hypertension are known complications of advanced COPD. We sought to identify genetic polymorphisms associated with these traits in a population of patients with severe COPD from the National Emphysema Treatment Trial (NETT).
In 389 participants from the NETT Genetics Ancillary Study, single-nucleotide polymorphisms (SNPs) were genotyped in five candidate genes previously associated with COPD susceptibility (EPHX1, SERPINE2, SFTPB, TGFB1, and GSTP1). Linear regression models were used to test for associations among these SNPs and three quantitative COPD-related traits (Pao2, Paco2, and pulmonary artery systolic pressure). Genes associated with hypoxemia were tested for replication in probands from the Boston Early-Onset COPD Study.
In the NETT Genetics Ancillary Study population, SNPs in microsomal epoxide hydrolase (EPHX1) [p = 0.01 to 0.04] and serpin peptidase inhibitor, clade E, member 2 (SERPINE2) [p = 0.04 to 0.008] were associated with hypoxemia. One SNP within surfactant protein B (SFTPB) was associated with pulmonary artery systolic pressure (p = 0.01). In probands from the Boston Early-Onset COPD Study, SNPs in EPHX1 and in SERPINE2 were associated with the requirement for supplemental oxygen.
In participants with severe COPD, SNPs in EPHX1 and SERPINE2 were associated with hypoxemia in two separate study populations, and SNPs from SFTPB were associated with pulmonary artery pressure in the NETT participants.
PMCID: PMC2906241  PMID: 19017876
case-control studies; COPD; genetics; phenotype; single-nucleotide polymorphism
25.  A report of cytokine polymorphisms and COPD risk in Xuan Wei, China 
Indoor air pollution has been documented as an important risk factor for chronic obstructive pulmonary disease (COPD), and inflammation is central to the development and progression of COPD. Single nucleotide polymorphisms (SNP) in some cytokine genes have been reported to be associated with COPD. We examined the association between 18 SNPs in 10 cytokine genes and COPD risk in a case-control study conducted in a population with high exposure to indoor smoky coal emissions. The study included 53 COPD cases and 122 healthy community controls. Carriers of the CSF2 117Ile allele had a 2.4-fold higher risk of COPD than the wild type (Thr/Thr) carriers (OR: 2.44; 95% CI: 1.10 – 5.41), and the AA genotype at IL8 -351 was associated with an increased risk of COPD (OR: 2.71; 95% CI: 1.04 – 7.04). When the combined effects of CSF2 117Ile and IL8 -351A were examined, individuals carrying at least one variant in both genes had a five-fold increased risk of COPD (OR: 5.14, 95% CI: 1.32 – 29.86). This study suggests that polymorphisms in both CSF2 and IL8 may play a role in the pathogenesis of COPD, at least in highly exposed populations. However, in view of our relatively small sample size, this study should be replicated in other populations with substantial exposure to indoor air pollutants such as polycyclic aromatic hydrocarbons (PAH) and particulate matter.
PMCID: PMC2639784  PMID: 17681858
COPD; Cytokine; CSF2; IL8; Single nucleotide polymorphism; Indoor air pollution

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