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1.  Genetic testing for respiratory disease: Are we there yet? 
The human genome project promised a revolution in health care – the development of ‘personalized medicine’, where knowledge of an individual’s genetic code enables the prediction of risk for specific diseases and the potential to alter that risk based on preventive measures and lifestyle modification. The present brief review provides a report card on the progress toward that goal with respect to respiratory disease. Should generalized population screening for genetic risk factors for respiratory disease be instituted? Or not?
PMCID: PMC3411388  PMID: 22891183
Asthma; Cystic fibrosis; COPD; Genetics; Human genome project; Screening
2.  Nitric oxide synthase polymorphisms, gene expression and lung function in chronic obstructive pulmonary disease 
Background
Due to the pleiotropic effects of nitric oxide (NO) within the lungs, it is likely that NO is a significant factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to test for association between single nucleotide polymorphisms (SNPs) in three NO synthase (NOS) genes and lung function, as well as to examine gene expression and protein levels in relation to the genetic variation.
Methods
One SNP in each NOS gene (neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3)) was genotyped in the Lung Health Study (LHS) and correlated with lung function. One SNP (rs1800779) was also analyzed for association with COPD and lung function in four COPD case–control populations. Lung tissue expression of NOS3 mRNA and protein was tested in individuals of known genotype for rs1800779. Immunohistochemistry of lung tissue was used to localize NOS3 expression.
Results
For the NOS3 rs1800779 SNP, the baseline forced expiratory volume in one second in the LHS was significantly higher in the combined AG + GG genotypic groups compared with the AA genotypic group. Gene expression and protein levels in lung tissue were significantly lower in subjects with the AG + GG genotypes than in AA subjects. NOS3 protein was expressed in the airway epithelium and subjects with the AA genotype demonstrated higher NOS3 expression compared with AG and GG individuals. However, we were not able to replicate the associations with COPD or lung function in the other COPD study groups.
Conclusions
Variants in the NOS genes were not associated with lung function or COPD status. However, the G allele of rs1800779 resulted in a decrease of NOS3 gene expression and protein levels and this has implications for the numerous disease states that have been associated with this polymorphism.
doi:10.1186/1471-2466-13-64
PMCID: PMC3827989  PMID: 24192154
Chronic obstructive pulmonary disease; Nitric oxide synthase; Polymorphism; Gene expression
4.  Lung eQTLs to Help Reveal the Molecular Underpinnings of Asthma 
PLoS Genetics  2012;8(11):e1003029.
Genome-wide association studies (GWAS) have identified loci reproducibly associated with pulmonary diseases; however, the molecular mechanism underlying these associations are largely unknown. The objectives of this study were to discover genetic variants affecting gene expression in human lung tissue, to refine susceptibility loci for asthma identified in GWAS studies, and to use the genetics of gene expression and network analyses to find key molecular drivers of asthma. We performed a genome-wide search for expression quantitative trait loci (eQTL) in 1,111 human lung samples. The lung eQTL dataset was then used to inform asthma genetic studies reported in the literature. The top ranked lung eQTLs were integrated with the GWAS on asthma reported by the GABRIEL consortium to generate a Bayesian gene expression network for discovery of novel molecular pathways underpinning asthma. We detected 17,178 cis- and 593 trans- lung eQTLs, which can be used to explore the functional consequences of loci associated with lung diseases and traits. Some strong eQTLs are also asthma susceptibility loci. For example, rs3859192 on chr17q21 is robustly associated with the mRNA levels of GSDMA (P = 3.55×10−151). The genetic-gene expression network identified the SOCS3 pathway as one of the key drivers of asthma. The eQTLs and gene networks identified in this study are powerful tools for elucidating the causal mechanisms underlying pulmonary disease. This data resource offers much-needed support to pinpoint the causal genes and characterize the molecular function of gene variants associated with lung diseases.
Author Summary
Recent genome-wide association studies (GWAS) have identified genetic variants associated with lung diseases. The challenge now is to find the causal genes in GWAS–nominated chromosomal regions and to characterize the molecular function of disease-associated genetic variants. In this paper, we describe an international effort to systematically capture the genetic architecture of gene expression regulation in human lung. By studying lung specimens from 1,111 individuals of European ancestry, we found a large number of genetic variants affecting gene expression in the lung, or lung expression quantitative trait loci (eQTL). These lung eQTLs will serve as an important resource to aid in the understanding of the molecular underpinnings of lung biology and its disruption in disease. To demonstrate the utility of this lung eQTL dataset, we integrated our data with previous genetic studies on asthma. Through integrative techniques, we identified causal variants and genes in GWAS–nominated loci and found key molecular drivers for asthma. We feel that sharing our lung eQTLs dataset with the scientific community will leverage the impact of previous large-scale GWAS on lung diseases and function by providing much needed functional information to understand the molecular changes introduced by the susceptibility genetic variants.
doi:10.1371/journal.pgen.1003029
PMCID: PMC3510026  PMID: 23209423
5.  Functional characterization of the matrix metalloproteinase-1 cigarette smoke-responsive region and association with the lung health study 
Respiratory Research  2012;13(1):79.
Background
Prior studies have demonstrated that the distal 1.5 kb of the MMP-1 promoter is fundamental in directing the induction of the MMP-1 gene by cigarette smoke.
Methods
To characterize the genetic variants in the MMP-1 cigarette smoke-responsive element, deep re-sequencing of this element was performed on DNA samples from participants in the Lung Health Study. Furthermore, evidence of Sp1 binding to the MMP-1 promoter was assessed using chromatin immunoprecipitation assays and the influence of cigarette smoke exposure on this interaction was evaluated in cultured human small airway epithelial cells.
Results
Ten polymorphisms (four novel) were detected in the cigarette smoke-responsive element. Chromatin immunoprecipitation assays to assess the protein-DNA interactions at Sp1 sites in the MMP-1 promoter showed increased binding to the Sp1 sites in the cigarette smoke-responsive element in small airway epithelial cells treated with cigarette smoke extract. In contrast, a Sp1 site outside of the element exhibited the opposite effect. None of the polymorphisms were more prevalent in the fast decliners versus the slow decliners (fast decliners = mean −4.14% decline in FEV1% predicted per year vs. decline in FEV1% predicted per year).
Conclusions
Sequencing analyses identified four novel polymorphisms within the cigarette smoke-responsive element of the MMP-1 promoter. This study identifies functional activity within the cigarette smoke-responsive element that is influenced by cigarette smoke and examines this region of the promoter within a small patient population.
doi:10.1186/1465-9921-13-79
PMCID: PMC3509005  PMID: 22992122
Chromatin immunoprecipitation; COPD; Metalloproteinase; Polymorphisms; Transcription factors
6.  Small-Airway Obstruction and Emphysema in Chronic Obstructive Pulmonary Disease 
The New England journal of medicine  2011;365(17):1567-1575.
BACKGROUND
The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway obstruction and emphysematous destruction in COPD.
METHODS
We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles.
RESULTS
On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in patients with GOLD stage 1 disease (P = 0.001), GOLD stage 2 disease (P = 0.02), and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patients with GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area of terminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). A comparison of the number of terminal bronchioles and dimensions at different levels of emphysematous destruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD (P<0.001).
CONCLUSIONS
These results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD. (Funded by the National Heart, Lung, and Blood Institute and others.)
doi:10.1056/NEJMoa1106955
PMCID: PMC3238466  PMID: 22029978
7.  Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD 
Human genetics  2012;132(1):79-90.
Rationale
Accelerated lung function decline is a key COPD phenotype; however its genetic control remains largely unknown.
Methods
We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European-American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry.
Measurements and Main Results
Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status.
Conclusions
We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
doi:10.1007/s00439-012-1219-6
PMCID: PMC3536920  PMID: 22986903
COPD; lung function decline; GWAS; genome wide association; genes; polymorphisms
8.  Differential Expression of Tissue Repair Genes in the Pathogenesis of Chronic Obstructive Pulmonary Disease 
Rationale: The airflow limitation that defines severity of chronic obstructive pulmonary disease (COPD) is caused by a combination of small airway obstruction and emphysematous lung destruction.
Objectives: To examine the hypothesis that small airway obstructive and emphysematous destructive lesions are produced by differential expression of genes associated with tissue repair.
Methods: The expression of 54 genes associated with repair of repetitively damaged tissue was measured in 136 paired samples of small bronchioles and surrounding lung tissue separated by laser capture microdissection. These samples were collected from 63 patients at different levels of disease severity who required surgery for either lung cancer or lung transplantation for very severe COPD. Gene expression was measured by quantitative polymerase chain reaction in these paired samples and compared with the FEV1 by linear regression analysis.
Measurements and Main Results: After corrections for false discovery rates, only 2 of 10 genes (serpin peptidase inhibitor/plasminogen activator inhibitor member 2 and matrix metalloproteinase [MMP] 10) increased, whereas 8 (MMP2, integrin-α1, vascular endothelial growth factor, a disintegrin and metallopeptidase domain 33, scatter factor/hepatocyte growth factor, tissue inhibitor of matrix metalloproteinase-2, fibronectin, and collagen 3α1) decreased in small airways in association with FEV1. In contrast, 8/12 genes (early growth response factor 1, MMP1, MMP9, MMP10, plasminogen activator urokinase, plasminogen activator urokinase receptor, tumor necrosis factor, and IL13) increased and 4/12 (MMP2, tissue inhibitor of matrix metalloproteinase-1, collagen 1α1, and transforming growth factor-β3) decreased in the surrounding lung tissue in association with progression of COPD.
Conclusions: The progression of COPD is associated with the differential expression of a cluster of genes that favor the degradation of the tissue surrounding the small conducting airways.
doi:10.1164/rccm.200812-1902OC
PMCID: PMC2894408  PMID: 20075389
emphysema; pulmonary disease, chronic obstructive; polymerase chain reaction; laser microdissection; nucleic acid amplification techniques
9.  Effect of gene environment interactions on lung function and cardiovascular disease in COPD 
Background:
The objective of this study was to determine if gene-environment interactions between cigarette smoking and interleukin-6 (IL6), interferon-γ (IFNG), interleukin-1β (IL1B), or interleukin-1 receptor antagonist (IL1RN) single nucleotide polymorphisms are associated with lung function decline and cardiovascular disease in chronic obstructive pulmonary disease (COPD).
Methods:
Single nucleotide polymorphisms (SNPs) in IL6, IFNG, IL1B, and IL1RN were genotyped in the Lung Health Study and correlated with rate of decline of forced expiratory volume in 1 second (FEV1) over 5 years, baseline FEV1, serum protein levels, cardiovascular disease, and interactions with smoking.
Results:
The IL6 rs2069825 single nucleotide polymorphism was associated with the rate of decline of prebronchodilator FEV1 (P = 0.049), and was found to have a significant interaction (P = 0.004) with mean number of cigarettes smoked per day. There was also a significant interaction of IFNG rs2069727 with smoking on prebronchodilator (P = 0.008) and postbronchodilator (P =0.01) FEV1. The IL6 polymorphism was also associated with cardiovascular disease in heterozygous individuals (P = 0.044), and was found to have a significant interaction with smoking (P = 0.024). None of the genetic variants were associated with their respective serum protein levels.
Conclusion:
The results suggest interactions of IL6 rs2069825 and IFNG rs2069727 single nucleotide polymorphisms with cigarette smoking on measures of lung function. The IL6 rs2069825 single nucleotide polymorphism also interacted with smoking to affect the risk of cardiovascular disease in COPD patients.
doi:10.2147/COPD.S18279
PMCID: PMC3144847  PMID: 21814463
gene-environment interactions; interleukin-6; forced expiratory volume in one second; cardiovascular disease; chronic obstructive pulmonary disease
10.  Decreased Fibronectin Production Significantly Contributes to Dysregulated Repair of Asthmatic Epithelium 
Rationale: Damage to airway epithelium is followed by deposition of extracellular matrix (ECM) and migration of adjacent epithelial cells. We have shown that epithelial cells from children with asthma fail to heal a wound in vitro.
Objectives: To determine whether dysregulated ECM production by the epithelium plays a role in aberrant repair in asthma.
Methods: Airway epithelial cells (AEC) from children with asthma (n = 36), healthy atopic control subjects (n = 23), and healthy nonatopic control subjects (n = 53) were investigated by microarray, gene expression and silencing, transcript regulation analysis, and ability to close mechanical wounds.
Measurements and Main Results: Time to repair a mechanical wound in vitro by AEC from healthy and atopic children was not significantly different and both were faster than AEC from children with asthma. Microarray analysis revealed differential expression of multiple gene sets associated with repair and remodeling in asthmatic AEC. Fibronectin (FN) was the only ECM component whose expression was significantly lower in asthmatic AEC. Expression differences were verified by quantitative polymerase chain reaction and ELISA, and reduced FN expression persisted in asthmatic cells over passage. Silencing of FN expression in nonasthmatic AEC inhibited wound repair, whereas addition of FN to asthmatic AEC restored reparative capacity. Asthmatic AEC failed to synthesize FN in response to wounding or cytokine/growth factor stimulation. Exposure to 5′, 2′deoxyazacytidine had no effect on FN expression and subsequent analysis of the FN promoter did not show evidence of DNA methylation.
Conclusions: These data show that the reduced capacity of asthmatic epithelial cells to secrete FN is an important contributor to the dysregulated AEC repair observed in these cells.
doi:10.1164/rccm.200907-1071OC
PMCID: PMC2862303  PMID: 20110557
fibronectin; asthma; epithelium; wound repair; inflammation
13.  ROLE OF GENETIC SUSCEPTIBILITY TO LATENT ADENOVIRAL INFECTION AND DECREASED LUNG FUNCTION 
Respiratory medicine  2009;103(11):1672-1680.
Background
Latent adenoviral infection may amplify cigarette smoke-induced lung inflammation and therefore play an important role in the development of chronic obstructive pulmonary disease (COPD). Adenoviruses can evade the human immune response via their 19-kDa protein (19K) which delays the expression of class I human leukocyte antigen (HLA) proteins. The 19K protein shows higher affinity to HLA-B7 and A2 compared with HLA-A1 and A3. The receptor for adenovirus (CXADR) and integrin β5 (ITGB5) are host factors which might affect adenovirus infection. Therefore, we investigated the contribution of HLA, CXADR, and ITGB5 genetic variants to the presence of the E1A gene and to level of lung function.
Methods
Study subjects were assayed for HLA-B7, A1, A2 and A3 by PCR-based assays using allele-specific primers. Polymorphisms of the CXADR and ITGB5 genes were genotyped by PCR-based restriction fragment length polymorphism assays. Detection of adenoviral E1A gene was performed by a real-time PCR TaqMan assay.
Results
E1A positive individuals have a lower FEV1 compared with E1A negative individuals. However, there was no significant difference in E1A positivity rate between the high (HLA-B7 and A2) and low (HLA-A1 and A3) 19K affinity groups. There was also no significant difference in FEV1 level between each affinity group. There was no significant difference in E1A positivity rate or lung function among the CXADR and ITGB5 genotypes.
Conclusions
Genetic variants in HLA, CXADR and ITGB5 do not influence latent adenoviral infections and are not associated with COPD.
doi:10.1016/j.rmed.2009.05.008
PMCID: PMC2757510  PMID: 19502044
14.  Quantification of lung surface area using computed tomography 
Respiratory Research  2010;11(1):153.
Objective
To refine the CT prediction of emphysema by comparing histology and CT for specific regions of lung. To incorporate both regional lung density measured by CT and cluster analysis of low attenuation areas for comparison with histological measurement of surface area per unit lung volume.
Methods
The histological surface area per unit lung volume was estimated for 140 samples taken from resected lung specimens of fourteen subjects. The region of the lung sampled for histology was located on the pre-operative CT scan; the regional CT median lung density and emphysematous lesion size were calculated using the X-ray attenuation values and a low attenuation cluster analysis. Linear mixed models were used to examine the relationships between histological surface area per unit lung volume and CT measures.
Results
The median CT lung density, low attenuation cluster analysis, and the combination of both were important predictors of surface area per unit lung volume measured by histology (p < 0.0001). Akaike's information criterion showed the model incorporating both parameters provided the most accurate prediction of emphysema.
Conclusion
Combining CT measures of lung density and emphysematous lesion size provides a more accurate estimate of lung surface area per unit lung volume than either measure alone.
doi:10.1186/1465-9921-11-153
PMCID: PMC2976969  PMID: 21040527
15.  Genetics and Genomics of Chronic Obstructive Pulmonary Disease 
Chronic obstructive pulmonary disease (COPD) fulfills criteria for a complex genetic disease in which environmental factors interact with multiple polymorphic genes to influence susceptibility. Finding the genes that influence susceptibility can be approached in hypothesis testing or unbiased study designs. In candidate gene association studies, genetic variation in, and/or levels of, expression of genes known or suspected to be involved in the pathogenesis of COPD are compared in affected and unaffected individuals. Although this approach is useful it is limited by our present knowledge of disease pathophysiology. Genomewide studies of gene expression and of genetic variation are now possible and are not constrained by our limited knowledge. Although both of these unbiased approaches are in their infancy, they have already provided exciting new avenues for future investigation and potentially now approaches to risk prediction and therapy.
doi:10.1513/pats.200904-021DS
PMCID: PMC3266048  PMID: 19741265
chronic obstructive pulmonary disease; genetics; genomics
16.  Associations of IL6 polymorphisms with lung function decline and COPD 
Thorax  2009;64(8):698-704.
Background
Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which likely plays an important role in the pathogenesis of COPD. There is a functional single nucleotide polymorphism (SNP), −174G/C, in the promoter region of IL6. We hypothesized that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers.
Methods
Seven and 5 SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in one second (FEV1) over 5 years and baseline FEV1 at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of 9 IL6 SNPs was genotyped in 389 COPD cases from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS).
Results
In the LHS, three IL6 SNPs were associated with FEV1 decline (0.023 ≤ P ≤ 0.041 in additive models). Among them the IL6_−174C allele was associated with rapid decline of lung function. The association was more significant in a genotype-based analysis (P = 0.006). In the NETT-NAS study, IL6_−174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_−174G/C, were associated with susceptibility to COPD (0.01 ≤ P ≤ 0.04 in additive genetic models).
Conclusion
Our results suggest that the IL6_−174G/C SNP is associated with rapid decline of FEV1 and susceptibility to COPD in smokers.
doi:10.1136/thx.2008.111278
PMCID: PMC2859187  PMID: 19359268
genetic polymorphism; IL6; forced expiratory volume in one second (FEV1); lung function; chronic obstructive pulmonary disease (COPD)
17.  Lack of association of TIM3 polymorphisms and allergic phenotypes 
BMC Medical Genetics  2009;10:62.
Background
T-cell immunoglobulin mucin-3 (TIM3) is a TH1-specific type 1 membrane protein that regulates TH1 proliferation and the development of immunological tolerance. TIM3 and its genetic variants have been suggested to play a role in regulating allergic diseases. Polymorphisms in the TIM3 promoter region have been reported to be associated with allergic phenotypes in several populations. The aims of this study were to examine whether genetic variation in the promoter region of TIM3 influenced transcription of the gene and risk for allergic phenotypes.
Methods
We performed 5' rapid amplification of cDNA ends and reverse transcription-polymerase chain reaction. We screened for polymorphisms in the promoter region. Deletion analysis was used to localize the promoter region of TIM3. Genotyping was performed by TaqMan assays in three asthma/allergy population samples.
Results
We found two regions with promoter activity in TIM3. One region was from -214 bp to +58 bp and the other from -1.6 kb to -914 bp relative to the transcription start site. None of the single nucleotide polymorphisms (SNPs) or haplotypes affected the transcriptional activity in reporter gene assays. No association between the SNPs and any phenotype was observed in the study cohorts.
Conclusion
Our findings indicate that SNPs and haplotypes in the TIM3 promoter region do not have a functional effect in vitro and are not associated with allergic diseases. These data suggest that polymorphisms in the TIM3 promoter region are unlikely to play an important role in susceptibility to allergic diseases.
doi:10.1186/1471-2350-10-62
PMCID: PMC2711936  PMID: 19566956
18.  Complex two-gene modulation of lung disease severity in children with cystic fibrosis 
The Journal of Clinical Investigation  2008;118(3):1040-1049.
Although cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-β1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.
doi:10.1172/JCI33754
PMCID: PMC2248329  PMID: 18292811
19.  Recent advances in asthma genetics 
Respiratory Research  2008;9(1):4.
There are over 100 genes that have been reported to be associated with asthma or related phenotypes. In 2006–2007 alone there were 53 novel candidate gene associations reported in the literature. Replication of genetic associations and demonstration of a functional mechanism for the associated variants are needed to confirm an asthma susceptibility gene. For most of the candidate genes there is little functional information. In a previous review by Hoffjan et al. published in 2003, functional information was reported for 40 polymorphisms and here we list another 22 genes which have such data. Some important genes such as filaggrin, interleukin-13, interleukin-17 and the cysteinyl leukotriene receptor-1 which not only were replicated by independent association studies but also have functional data are reviewed in this article.
doi:10.1186/1465-9921-9-4
PMCID: PMC2244620  PMID: 18197984
20.  Refining Susceptibility Loci of Chronic Obstructive Pulmonary Disease with Lung eqtls 
PLoS ONE  2013;8(7):e70220.
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.
doi:10.1371/journal.pone.0070220
PMCID: PMC3728203  PMID: 23936167
21.  Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study 
Respiratory Research  2006;7(1):76.
Background
Alpha-defensins, which are major constituents of neutrophil azurophilic granules, and beta-defensins, which are expressed in airway epithelial cells, could contribute to the pathogenesis of chronic obstructive pulmonary disease by amplifying cigarette smoke-induced and infection-induced inflammatory reactions leading to lung injury. In Japanese and Chinese populations, two different beta-defensin-1 polymorphisms have been associated with chronic obstructive pulmonary disease phenotypes. We conducted population-based association studies to test whether alpha-defensin and beta-defensin polymorphisms influenced smokers' susceptibility to lung function decline and susceptibility to lower respiratory infection in two groups of white participants in the Lung Health Study (275 = fast decline in lung function and 304 = no decline in lung function).
Methods
Subjects were genotyped for the alpha-defensin-1/alpha-defensin-3 copy number polymorphism and four beta-defensin-1 polymorphisms (G-20A, C-44G, G-52A and Val38Ile).
Results
There were no associations between individual polymorphisms or imputed haplotypes and rate of decline in lung function or susceptibility to infection.
Conclusion
These findings suggest that, in a white population, the defensin polymorphisms tested may not be of importance in determining who develops abnormally rapid lung function decline or is susceptible to developing lower respiratory infections.
doi:10.1186/1465-9921-7-76
PMCID: PMC1523340  PMID: 16700921
22.  DNA Methylation Profiles of Airway Epithelial Cells and PBMCs from Healthy, Atopic and Asthmatic Children 
PLoS ONE  2012;7(9):e44213.
Background
Allergic inflammation is commonly observed in a number of conditions that are associated with atopy including asthma, eczema and rhinitis. However, the genetic, environmental or epigenetic factors involved in these conditions are likely to be different. Epigenetic modifications, such as DNA methylation, can be influenced by the environment and result in changes to gene expression.
Objectives
To characterize the DNA methylation pattern of airway epithelial cells (AECs) compared to peripheral blood mononuclear cells (PBMCs) and to discern differences in methylation within each cell type amongst healthy, atopic and asthmatic subjects.
Methods
PBMCs and AECs from bronchial brushings were obtained from children undergoing elective surgery for non-respiratory conditions. The children were categorized as atopic, atopic asthmatic, non-atopic asthmatic or healthy controls. Extracted DNA was bisulfite treated and 1505 CpG loci across 807 genes were analyzed using the Illumina GoldenGate Methylation Cancer Panel I. Gene expression for a subset of genes was performed using RT-PCR.
Results
We demonstrate a signature set of CpG sites that are differentially methylated in AECs as compared to PBMCs regardless of disease phenotype. Of these, 13 CpG sites were specific to healthy controls, 8 sites were only found in atopics, and 6 CpGs were unique to asthmatics. We found no differences in the methylation status of PBMCs between disease phenotypes. In AECs derived from asthmatics compared to atopics, 8 differentially methylated sites were identified including CpGs in STAT5A and CRIP1. We demonstrate STAT5A gene expression is decreased whereas CRIP1 gene expression is elevated in the AECs from asthmatic compared to both healthy and atopic subjects.
Discussion
We characterized a cell specific DNA methylation signature for AECs compared to PBMCs regardless of asthmatic or atopic status. Our data highlight the importance of understanding DNA methylation in the epithelium when studying the epithelial contribution to asthma.
doi:10.1371/journal.pone.0044213
PMCID: PMC3435400  PMID: 22970180
23.  Effect of heme oxygenase-1 polymorphisms on lung function and gene expression 
BMC Medical Genetics  2011;12:117.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2350-12-117
PMCID: PMC3180266  PMID: 21902835
Heme oxygenase; polymorphism; chronic obstructive pulmonary disease
24.  Multistudy Fine Mapping of Chromosome 2q Identifies XRCC5 as a Chronic Obstructive Pulmonary Disease Susceptibility Gene 
Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.
Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.
Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.
Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 × 10−5 across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.
Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.
doi:10.1164/rccm.200910-1586OC
PMCID: PMC2937234  PMID: 20463177
emphysema; genetic linkage; metaanalysis; single nucleotide polymorphism
25.  Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results 
Human genetics  2009;126(6):763-778.
Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16–20% of CF newborns, providing linkage and association results from large family and case–control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case–control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy–Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up.
doi:10.1007/s00439-009-0724-8
PMCID: PMC2888886  PMID: 19662435

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