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Forder A, Zhuang R, Souza VGP, Brockley LJ, Pewarchuk ME, Telkar N, Stewart GL, Benard K, Marshall EA, Reis PP, Lam WL. Mechanisms Contributing to the Comorbidity of COPD and Lung Cancer. Int J Mol Sci 2023; 24:ijms24032859. [PMID: 36769181 PMCID: PMC9918127 DOI: 10.3390/ijms24032859] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/18/2023] [Accepted: 01/22/2023] [Indexed: 02/05/2023] Open
Abstract
Lung cancer and chronic obstructive pulmonary disease (COPD) often co-occur, and individuals with COPD are at a higher risk of developing lung cancer. While the underlying mechanism for this risk is not well understood, its major contributing factors have been proposed to include genomic, immune, and microenvironment dysregulation. Here, we review the evidence and significant studies that explore the mechanisms underlying the heightened lung cancer risk in people with COPD. Genetic and epigenetic changes, as well as the aberrant expression of non-coding RNAs, predispose the lung epithelium to carcinogenesis by altering the expression of cancer- and immune-related genes. Oxidative stress generated by tobacco smoking plays a role in reducing genomic integrity, promoting epithelial-mesenchymal-transition, and generating a chronic inflammatory environment. This leads to abnormal immune responses that promote cancer development, though not all smokers develop lung cancer. Sex differences in the metabolism of tobacco smoke predispose females to developing COPD and accumulating damage from oxidative stress that poses a risk for the development of lung cancer. Dysregulation of the lung microenvironment and microbiome contributes to chronic inflammation, which is observed in COPD and known to facilitate cancer initiation in various tumor types. Further, there is a need to better characterize and identify the proportion of individuals with COPD who are at a high risk for developing lung cancer. We evaluate possible novel and individualized screening strategies, including biomarkers identified in genetic studies and exhaled breath condensate analysis. We also discuss the use of corticosteroids and statins as chemopreventive agents to prevent lung cancer. It is crucial that we optimize the current methods for the early detection and management of lung cancer and COPD in order to improve the health outcomes for a large affected population.
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Affiliation(s)
- Aisling Forder
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Rebecca Zhuang
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Vanessa G P Souza
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
- Molecular Oncology Laboratory, Experimental Research Unit, School of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil
| | - Liam J Brockley
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Michelle E Pewarchuk
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Nikita Telkar
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
- British Columbia Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada
| | - Greg L Stewart
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Katya Benard
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
| | - Erin A Marshall
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Patricia P Reis
- Molecular Oncology Laboratory, Experimental Research Unit, School of Medicine, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil
| | - Wan L Lam
- British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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Williams PT. Spirometric traits show quantile-dependent heritability, which may contribute to their gene-environment interactions with smoking and pollution. PeerJ 2020; 8:e9145. [PMID: 32461834 PMCID: PMC7233273 DOI: 10.7717/peerj.9145] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 04/17/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND "Quantile-dependent expressivity" refers to a genetic effect that is dependent upon whether the phenotype (e.g., spirometric data) is high or low relative to its population distribution. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and the FEV1/FVC ratio are moderately heritable spirometric traits. The aim of the analyses is to test whether their heritability (h2 ) is constant over all quantiles of their distribution. METHODS Quantile regression was applied to the mean age, sex, height and smoking-adjusted spirometric data over multiple visits in 9,993 offspring-parent pairs and 1,930 sibships from the Framingham Heart Study to obtain robust estimates of offspring-parent (βOP), offspring-midparent (βOM), and full-sib regression slopes (βFS). Nonparametric significance levels were obtained from 1,000 bootstrap samples. βOPs were used as simple indicators of quantile-specific heritability (i.e., h 2 = 2βOP/(1+rspouse), where rspouse was the correlation between spouses). RESULTS βOP ± standard error (SE) decreased by 0.0009 ± 0.0003 (P = 0.003) with every one-percent increment in the population distribution of FEV1/FVC, i.e., βOP ± SE were: 0.182 ± 0.031, 0.152 ± 0.015; 0.136 ± 0.011; 0.121 ± 0.013; and 0.099 ± 0.013 at the 10th, 25th, 50th, 75th, and 90th percentiles of the FEV1/FVC distribution, respectively. These correspond to h2 ± SEs of 0.350 ± 0.060 at the 10th, 0.292 ± 0.029 at the 25th, 0.262 ± 0.020 at the 50th, 0.234 ± 0.025 at the 75th, and 0.191 ± 0.025 at the 90th percentiles of the FEV1/FVC ratio. Maximum mid-expiratory flow (MMEF) h2 ± SEs increased 0.0025 ± 0.0007 (P = 0.0004) with every one-percent increment in its distribution, i.e.: 0.467 ± 0.046, 0.467 ± 0.033, 0.554 ± 0.038, 0.615 ± 0.042, and 0.675 ± 0.060 at the 10th, 25th, 50th, 75th, and 90th percentiles of its distribution. This was due to forced expiratory flow at 75% of FVC (FEF75%), whose quantile-specific h2 increased an average of 0.0042 ± 0.0008 for every one-percent increment in its distribution. It is speculated that previously reported gene-environment interactions may be partially attributable to quantile-specific h2 , i.e., greater heritability in individuals with lower FEV1/FVC due to smoking or airborne particles exposure vs. nonsmoking, unexposed individuals. CONCLUSION Heritabilities of FEV1/FVC, MMEF, and FEF75% from quantile-regression of offspring-parent and sibling spirometric data suggest their quantile-dependent expressivity.
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Affiliation(s)
- Paul T. Williams
- Molecular Biophysics & Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, United States of America
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A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle. J Allergy Clin Immunol 2018; 142:749-764.e3. [PMID: 29307657 PMCID: PMC6172038 DOI: 10.1016/j.jaci.2017.12.974] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 12/13/2017] [Accepted: 12/16/2017] [Indexed: 12/20/2022]
Abstract
Chromosome 17q12–21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12–21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus. (J Allergy Clin Immunol 2018;142:749–64.)
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Forno E, Sordillo J, Brehm J, Chen W, Benos T, Yan Q, Avila L, Soto-Quirós M, Cloutier MM, Colón-Semidey A, Alvarez M, Acosta-Pérez E, Weiss ST, Litonjua AA, Canino G, Celedón JC. Genome-wide interaction study of dust mite allergen on lung function in children with asthma. J Allergy Clin Immunol 2017; 140:996-1003.e7. [PMID: 28167095 DOI: 10.1016/j.jaci.2016.12.967] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 11/25/2016] [Accepted: 12/12/2016] [Indexed: 12/28/2022]
Abstract
BACKGROUND Childhood asthma is likely the result of gene-by-environment (G × E) interactions. Dust mite is a known risk factor for asthma morbidity. Yet, there have been no genome-wide G × E studies of dust mite allergen on asthma-related phenotypes. OBJECTIVE We sought to identify genetic variants whose effects on lung function in children with asthma are modified by the level of dust mite allergen exposure. METHODS A genome-wide interaction analysis of dust mite allergen level and lung function was performed in a cohort of Puerto Rican children with asthma (Puerto Rico Genetics of Asthma and Lifestyle [PRGOAL]). Replication was attempted in 2 independent cohorts, the Childhood Asthma Management Program (CAMP) and the Genetics of Asthma in Costa Rica Study. RESULTS Single nucleotide polymorphism (SNP) rs117902240 showed a significant interaction effect on FEV1 with dust mite allergen level in PRGOAL (interaction P = 3.1 × 10-8), and replicated in the same direction in CAMP white children and CAMP Hispanic children (combined interaction P = .0065 for replication cohorts and 7.4 × 10-9 for all cohorts). Rs117902240 was positively associated with FEV1 in children exposed to low dust mite allergen levels, but negatively associated with FEV1 in children exposed to high levels. This SNP is on chromosome 8q24, adjacent to a binding site for CCAAT/enhancer-binding protein beta, a transcription factor that forms part of the IL-17 signaling pathway. None of the SNPs identified for FEV1/forced vital capacity replicated in the independent cohorts. CONCLUSIONS Dust mite allergen exposure modifies the estimated effect of rs117902240 on FEV1 in children with asthma. Analysis of existing data suggests that this SNP may have transcription factor regulatory functions.
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Affiliation(s)
- Erick Forno
- Division of Pediatric Pulmonary Medicine, Allergy, and Immunology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pa; University of Pittsburgh School of Medicine, Pittsburgh, Pa
| | - Joanne Sordillo
- Channing Division of Network Medicine, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Mass
| | - John Brehm
- Division of Pediatric Pulmonary Medicine, Allergy, and Immunology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pa; University of Pittsburgh School of Medicine, Pittsburgh, Pa
| | - Wei Chen
- Division of Pediatric Pulmonary Medicine, Allergy, and Immunology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pa; University of Pittsburgh School of Medicine, Pittsburgh, Pa
| | - Takis Benos
- University of Pittsburgh School of Medicine, Pittsburgh, Pa
| | - Qi Yan
- Division of Pediatric Pulmonary Medicine, Allergy, and Immunology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pa; University of Pittsburgh School of Medicine, Pittsburgh, Pa
| | - Lydiana Avila
- Department of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica
| | - Manuel Soto-Quirós
- Department of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica
| | - Michelle M Cloutier
- Department of Pediatrics, University of Connecticut Health Center, Farmington, Conn
| | | | - Maria Alvarez
- Department of Pediatrics, University of Puerto Rico, San Juan, Puerto Rico
| | - Edna Acosta-Pérez
- Behavioral Sciences Research Institute, University of Puerto Rico, San Juan, Puerto Rico
| | - Scott T Weiss
- Channing Division of Network Medicine, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Mass
| | - Augusto A Litonjua
- Channing Division of Network Medicine, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Mass
| | - Glorisa Canino
- Behavioral Sciences Research Institute, University of Puerto Rico, San Juan, Puerto Rico
| | - Juan C Celedón
- Division of Pediatric Pulmonary Medicine, Allergy, and Immunology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pa; University of Pittsburgh School of Medicine, Pittsburgh, Pa.
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Li LSK, Paquet C, Johnston K, Williams MT. "What are my chances of developing COPD if one of my parents has the disease?" A systematic review and meta-analysis of prevalence of co-occurrence of COPD diagnosis in parents and offspring. Int J Chron Obstruct Pulmon Dis 2017; 12:403-415. [PMID: 28182144 PMCID: PMC5279828 DOI: 10.2147/copd.s123933] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Introduction Intergenerational associations in chronic obstructive pulmonary disease (COPD) have been well recognized and may result from genetic, gene environment, or exposure to life course factors. Consequently, adult offspring of parents with COPD may be at a greater risk of developing COPD. The aim of this study was to review the prevalence of co-occurrence of COPD in adult offspring with one or both parents having COPD independent of specific genetic variations. Methods In total, five databases were searched for original studies in which prevalence of COPD was reported in both offspring (children) and one or both parents. Studies were excluded if COPD was not clearly defined, COPD was linked to specific genetic variations, COPD was combined with other chronic respiratory conditions, or estimates included other first-degree relatives. Data extraction (ie, sample characteristics, prevalence of COPD, and odds ratio [OR] if reported) was completed by two independent reviewers. A meta-analysis of prevalence and OR was conducted, where possible. Results Of the 3,382 citations, 129 full texts were reviewed to include eight studies (six case–control, one cross-sectional, and one cohort) reflecting either prevalence of COPD in offspring of parents with COPD (descendent approach, n=3), which ranged from 0% to 17.3%, or prevalence of people with COPD reporting positive parental history of COPD (antecedent approach, n=5), for which the pooled prevalence was 28.6%. Offspring of people with COPD had 1.57 times greater odds (95% confidence interval =1.29–1.93; P<0.001) of having COPD compared with people not having a parental history of COPD. Conclusion The prevalence of COPD in adult offspring of people with COPD is greater than population-based estimates, and the ORs indicate a higher risk in this group. This offers clinicians a potential strategy for opportunistic screening, early identification, and intervention in this at-risk group.
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Affiliation(s)
- Lok Sze Katrina Li
- School of Health Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia
| | - Catherine Paquet
- Center for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia
| | - Kylie Johnston
- School of Health Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia
| | - Marie T Williams
- Alliance for Research in Exercise, Nutrition and Activity (ARENA), Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia
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Genetic Predisposition to COPD: Are There Any Relevant Genes Determining the Susceptibility to Smoking? ACTA ACUST UNITED AC 2016. [DOI: 10.1007/978-981-10-0839-9_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Abstract
Adhesion G protein-coupled receptors (aGPCRs) have a long evolutionary history dating back to very basal unicellular eukaryotes. Almost every vertebrate is equipped with a set of different aGPCRs. Genomic sequence data of several hundred extinct and extant species allows for reconstruction of aGPCR phylogeny in vertebrates and non-vertebrates in general but also provides a detailed view into the recent evolutionary history of human aGPCRs. Mining these sequence sources with bioinformatic tools can unveil many facets of formerly unappreciated aGPCR functions. In this review, we extracted such information from the literature and open public sources and provide insights into the history of aGPCR in humans. This includes comprehensive analyses of signatures of selection, variability of human aGPCR genes, and quantitative traits at human aGPCR loci. As indicated by a large number of genome-wide genotype-phenotype association studies, variations in aGPCR contribute to specific human phenotypes. Our survey demonstrates that aGPCRs are significantly involved in adaptation processes, phenotype variations, and diseases in humans.
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Affiliation(s)
- Peter Kovacs
- Integrated Research and Treatment Center (IFB) AdiposityDiseases, Medical Faculty, University of Leipzig, Liebigstr. 21, Leipzig, 04103, Germany.
| | - Torsten Schöneberg
- Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, Leipzig, 04103, Germany.
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Schwartz AG, Cote ML. Epidemiology of Lung Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 893:21-41. [PMID: 26667337 DOI: 10.1007/978-3-319-24223-1_2] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Lung cancer continues to be one of the most common causes of cancer death despite understanding the major cause of the disease: cigarette smoking. Smoking increases lung cancer risk 5- to 10-fold with a clear dose-response relationship. Exposure to environmental tobacco smoke among nonsmokers increases lung cancer risk about 20%. Risks for marijuana and hookah use, and the new e-cigarettes, are yet to be consistently defined and will be important areas for continued research as use of these products increases. Other known environmental risk factors include exposures to radon, asbestos, diesel, and ionizing radiation. Host factors have also been associated with lung cancer risk, including family history of lung cancer, history of chronic obstructive pulmonary disease and infections. Studies to identify genes associated with lung cancer susceptibility have consistently identified chromosomal regions on 15q25, 6p21 and 5p15 associated with lung cancer risk. Risk prediction models for lung cancer typically include age, sex, cigarette smoking intensity and/or duration, medical history, and occupational exposures, however there is not yet a risk prediction model currently recommended for general use. As lung cancer screening becomes more widespread, a validated model will be needed to better define risk groups to inform screening guidelines.
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Affiliation(s)
- Ann G Schwartz
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
| | - Michele L Cote
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
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Family-Based Association Study of Pulmonary Function in a Population in Northeast Asia. PLoS One 2015; 10:e0139716. [PMID: 26430897 PMCID: PMC4592257 DOI: 10.1371/journal.pone.0139716] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Accepted: 09/15/2015] [Indexed: 12/22/2022] Open
Abstract
The spirometric measurement of pulmonary function by measuring the forced expiratory volume in one second (FEV1) is a heritable trait that reflects the physiological condition of the lung and airways. Genome-wide linkage and association studies have identified a number of genes and genetic loci associated with pulmonary function. However, limited numbers of studies have been reported for Asian populations. In this study, we aimed to investigate genetic evidence of pulmonary function in a population in northeast Asia. We conducted a family-based association test with 706 GENDISCAN study participants from 72 Mongolian families to determine candidate genetic determinants of pulmonary function. For the replication, we chose seven candidate single nucleotide polymorphisms (SNPs) from the 5 loci, and tested 1062 SNPs for association with FEV1 from 2,729 subjects of the Korea Healthy Twin study. We identified TMEM132C as a potential candidate gene at 12q24.3, which is a previously reported locus of asthma and spirometric indices. We also found two adjacent candidate genes (UNC93A and TTLL2) in the 6q27 region, which has been previously identified as a pulmonary function locus in the Framingham cohort study. Our findings suggest that novel candidate genes (TMEM132C, UNC93A and TTLL2) in two different regions are associated with pulmonary function in a population in northeast Asia.
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Ortega VE, Kumar R. The Effect of Ancestry and Genetic Variation on Lung Function Predictions: What Is "Normal" Lung Function in Diverse Human Populations? Curr Allergy Asthma Rep 2015; 15:16. [PMID: 26130473 DOI: 10.1007/s11882-015-0516-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Lung function measures are an invaluable screening test for respiratory health and have been associated with the morbidity and mortality related to different airway disease as well as all-cause mortality. Currently, reference values for spirometric measurements are obtained using equations derived from individual ethnic or racial groups. The rapid expansion of more racially and ethnically diverse populations will challenge current race-based lung function reference equations. Recent international general population studies and ancestry-based genetic studies have found that ancestry and genetic variation are determinants of lung function and have suggested a role for genetic ancestry or gene variants in future lung function reference equations. In this review, we discuss the potential limitations of current lung function reference equations in a global society which is becoming more ethnically, racially, and, thus, genetically diverse. We also focus on how an individual's ancestral background or genetic profile could provide the basis for more accurate, personalized predictions of an individual's baseline lung function.
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Affiliation(s)
- Victor E Ortega
- Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA,
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Durham AL, Adcock IM. The relationship between COPD and lung cancer. Lung Cancer 2015; 90:121-7. [PMID: 26363803 PMCID: PMC4718929 DOI: 10.1016/j.lungcan.2015.08.017] [Citation(s) in RCA: 301] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 08/24/2015] [Accepted: 08/27/2015] [Indexed: 02/07/2023]
Abstract
COPD is a risk factor for lung cancer beyond their shared aetiology. Both are driven by oxidative stress. Both are linked to cellular aging, senescence and telomere shortening. Both have been linked to genetic predisposition. Both show altered epigenetic regulation of gene expression. Both COPD and lung cancer are major worldwide health concerns owing to cigarette smoking, and represent a huge, worldwide, preventable disease burden. Whilst the majority of smokers will not develop either COPD or lung cancer, they are closely related diseases, occurring as co-morbidities at a higher rate than if they were independently triggered by smoking. Lung cancer and COPD may be different aspects of the same disease, with the same underlying predispositions, whether this is an underlying genetic predisposition, telomere shortening, mitochondrial dysfunction or premature aging. In the majority of smokers, the burden of smoking may be dealt with by the body’s defense mechanisms: anti-oxidants such as superoxide dismutases, anti-proteases and DNA repair mechanisms. However, in the case of both diseases these fail, leading to cancer if mutations occur or COPD if damage to the cell and proteins becomes too great. Alternatively COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage, chronic exposure to pro-inflammatory cytokines, repression of the DNA repair mechanisms and increased cellular proliferation. Understanding the mechanisms that drive these processes in primary cells from patients with these diseases along with better disease models is essential for the development of new treatments.
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Affiliation(s)
- A L Durham
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, UK.
| | - I M Adcock
- Airway Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, UK
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Thyagarajan B, Wojczynski M, Minster RL, Sanders J, Barral S, Christiansen L, Barr RG, Newman A. Genetic variants associated with lung function: the long life family study. Respir Res 2014; 15:134. [PMID: 25409777 PMCID: PMC4228089 DOI: 10.1186/s12931-014-0134-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 10/16/2014] [Indexed: 11/11/2022] Open
Abstract
Background Reduced forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) are strong predictors of mortality and lung function is higher among individuals with exceptional longevity. However, genetic factors associated with lung function in individuals with exceptional longevity have not been identified. Method We conducted a genome wide association study (GWAS) to identify novel genetic variants associated with lung function in the Long Life Family Study (LLFS) (n = 3,899). Replication was performed using data from the CHARGE/SpiroMeta consortia. The association between SNPs and FEV1 and FEV1/FVC was analyzed using a linear mixed effects model adjusted for age, age2, sex, height, field center, ancestry principal components and kinship structure to adjust for family relationships separately for ever smokers and never smokers. In the linkage analysis, we used the residuals of the FEV1 and FEV1/FVC, adjusted for age, sex, height, ancestry principal components (PCs), smoking status, pack-years, and field center. Results We identified nine SNPs in strong linkage disequilibrium in the CYP2U1 gene to be associated with FEV1 and a novel SNP (rs889574) associated with FEV1/FVC, none of which were replicated in the CHARGE/SpiroMeta consortia. Using linkage analysis, we identified a novel linkage peak in chromosome 2 at 219 cM for FEV1/FVC (LOD: 3.29) and confirmed a previously reported linkage peak in chromosome 6 at 28 cM (LOD: 3.33) for FEV1. Conclusion Future studies need to identify the rare genetic variants underlying the linkage peak in chromosome 6 for FEV1. Electronic supplementary material The online version of this article (doi:10.1186/s12931-014-0134-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, University of Minnesota, 515 Delaware Street SE, 1-136 Moos Towers, Minneapolis 55455, MN, USA.
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Poon AH, Houseman EA, Ryan L, Sparrow D, Vokonas PS, Litonjua AA. Variants of asthma and chronic obstructive pulmonary disease genes and lung function decline in aging. J Gerontol A Biol Sci Med Sci 2014; 69:907-13. [PMID: 24253534 PMCID: PMC4111635 DOI: 10.1093/gerona/glt179] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Accepted: 10/04/2013] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND A substantial proportion of the general population has low lung function, and lung function is known to decrease as we age. Low lung function is a feature of several pulmonary disorders, such as uncontrolled asthma and chronic obstructive pulmonary disease. The objective of this study is to investigate the association of polymorphisms in asthma and chronic obstructive pulmonary disease candidate genes with rates of lung function decline in a general population sample of aging men. METHODS We analyzed data from a cohort of 1,047 Caucasian men without known lung disease, who had a mean of 25 years of lung function data, and on whom DNA was available. The cohort was randomly divided into two groups, and we tested a total of 940 single-nucleotide polymorphisms in 44 asthma and chronic obstructive pulmonary disease candidate genes in the first group (testing cohort, n = 545) for association with change in forced expiratory volume in 1 second over time. RESULTS One hundred nineteen single-nucleotide polymorphisms that showed nominal associations in the testing cohort were then genotyped and tested in the second group (replication cohort, n = 502). Evidence for association from the testing and replication cohorts were combined, and after adjustment for multiple testing, seven variants of three genes (DPP10, NPSR1, and ADAM33) remained significantly associated with change in forced expiratory volume in 1 second over time. CONCLUSIONS Our findings that genetic variants of genes involved in asthma and chronic obstructive pulmonary disease are associated with lung function decline in normal aging participants suggest that similar genetic mechanisms may underlie lung function decline in both disease and normal aging processes.
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Affiliation(s)
- Audrey H Poon
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Meakins Christie Laboratories, McGill University Health Centre (MUHC), Montreal, Quebec, Canada
| | - E Andres Houseman
- College of Public Health and Human Sciences, Oregon State University, Corvallis
| | - Louise Ryan
- Division of Mathematics, Informatics and Statistics (CMIS), Commonwealth Scientic and Industrial Research Organisation (CSIRO), North Ryde, New South Wales, Australia
| | - David Sparrow
- Normative Aging Study, VA Boston Healthcare System, Massachusetts. Department of Medicine at Boston University School of Medicine, Masssachusetts
| | - Pantel S Vokonas
- Normative Aging Study, VA Boston Healthcare System, Massachusetts. Department of Medicine at Boston University School of Medicine, Masssachusetts
| | - Augusto A Litonjua
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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Green CE, Turner AM. Role of chronic obstructive pulmonary disease in lung cancer pathogenesis. World J Respirol 2013; 3:67-76. [DOI: 10.5320/wjr.v3.i3.67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 08/26/2013] [Accepted: 09/04/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) and lung cancer are two important smoking related conditions. However, COPD has been shown to be an independent risk factor for lung cancer regardless of smoking history, suggesting that COPD and lung cancer may share a common pathogenesis. This review summarizes the epidemiology of lung cancer and COPD briefly, as well as discussing the potential for shared genetic risk, and shared genomic mechanisms, such as epigenetic changes or DNA damage induced by smoking. How key areas of COPD pathogenesis, such as inflammation, oxidative stress and protease imbalance may contribute to subsequent development of cancer will also be covered. Finally the possibility that consequences of COPD, such as hypoxia, influence carcinogenesis will be reviewed. By understanding the pathogenesis of COPD and lung cancer in detail it is possible that new treatments may be developed and the risk of lung cancer in COPD may be reduced.
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15
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Howden R, Kleeberger SR. Genetic and Environmental Influences on Gas Exchange. Compr Physiol 2012; 2:2595-614. [DOI: 10.1002/cphy.c110060] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Abstract
Chronic obstructive pulmonary disease (COPD) and lung cancer represent two diseases that share a strong risk factor in smoking, and COPD increases risk of lung cancer even after adjusting for the effects of smoking. These diseases not only occur jointly within an individual but also there is evidence of shared occurrence within families. Understanding the genetic contributions to these diseases, both individually and jointly, is needed to identify the highest risk group for screening and targeted prevention, as well as aiding in the development of targeted treatments. The chromosomal regions that have been identified as being associated either jointly or independently with lung cancer, COPD, nicotine addiction, and lung function are presented. Studies jointly measuring genetic variation in lung cancer and COPD have been limited by the lack of detailed COPD diagnosis and severity data in lung cancer populations, the lack of lung cancer-specific phenotypes (histology and tumor markers) in COPD populations, and the lack of inclusion of minorities. African Americans, who smoke fewer cigarettes per day and have different linkage disequilibrium and disease patterns than whites, and Asians, also with different patterns of exposure to lung carcinogens and linkage patterns, will provide invaluable information to better understand shared and independent genetic contributions to lung cancer and COPD to more fully define the highest risk group of individuals who will most benefit from screening and to develop molecular signatures to aid in targeted treatment and prevention efforts.
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17
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Aldrich MC, Kumar R, Colangelo LA, Williams LK, Sen S, Kritchevsky SB, Meibohm B, Galanter J, Hu D, Gignoux CR, Liu Y, Harris TB, Ziv E, Zmuda J, Garcia M, Leak TS, Foreman MG, Smith LJ, Fornage M, Liu K, Burchard EG. Genetic ancestry-smoking interactions and lung function in African Americans: a cohort study. PLoS One 2012; 7:e39541. [PMID: 22737244 PMCID: PMC3380861 DOI: 10.1371/journal.pone.0039541] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 05/22/2012] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Smoking tobacco reduces lung function. African Americans have both lower lung function and decreased metabolism of tobacco smoke compared to European Americans. African ancestry is also associated with lower pulmonary function in African Americans. We aimed to determine whether African ancestry modifies the association between smoking and lung function and its rate of decline in African Americans. METHODOLOGY/PRINCIPAL FINDINGS We evaluated a prospective ongoing cohort of 1,281 African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study initiated in 1997. We also examined an ongoing prospective cohort initiated in 1985 of 1,223 African Americans in the Coronary Artery Disease in Young Adults (CARDIA) Study. Pulmonary function and tobacco smoking exposure were measured at baseline and repeatedly over the follow-up period. Individual genetic ancestry proportions were estimated using ancestry informative markers selected to distinguish European and West African ancestry. African Americans with a high proportion of African ancestry had lower baseline forced expiratory volume in one second (FEV₁) per pack-year of smoking (-5.7 ml FEV₁/ smoking pack-year) compared with smokers with lower African ancestry (-4.6 ml in FEV₁/ smoking pack-year) (interaction P value = 0.17). Longitudinal analyses revealed a suggestive interaction between smoking, and African ancestry on the rate of FEV(1) decline in Health ABC and independently replicated in CARDIA. CONCLUSIONS/SIGNIFICANCE African American individuals with a high proportion of African ancestry are at greater risk for losing lung function while smoking.
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Affiliation(s)
- Melinda C Aldrich
- Division of Epidemiology, Department of Thoracic Surgery, Vanderbilt University, Nashville, Tennessee, United States of America.
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18
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Prevot G, Plat G, Mazieres J. [COPD and lung cancer: epidemiological and biological links]. Rev Mal Respir 2012; 29:545-56. [PMID: 22542412 DOI: 10.1016/j.rmr.2011.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Accepted: 08/23/2011] [Indexed: 10/28/2022]
Abstract
Lung cancer and chronic obstructive lung disease (COPD) are two common fatal diseases. Apart from their common link to tobacco, these two diseases are usually considered to be the result of separate distinct mechanisms. In the past 15 years, numerous studies have produced arguments in favour of a relationship between these two pathologies that goes beyond a simple addition of risk factors. At the epidemiological level, there are data that demonstrate an increased incidence of bronchial carcinoma in patients with COPD. The links between these two pathologies are still unexplained but there are numerous arguments supporting a common physiopathology. Common genetic and epigenetic abnormalities, mechanical factors and signalisation pathways have been quoted. COPD and lung cancer appear to be two diseases possessing a genetic basis that creates a predisposition to environmental or toxic assaults, resulting in a different clinical manifestation in each disease. Consequently, improvements in the management of these two diseases will involve a more intensive investigation of their physiopathology, and require a closer collaboration between research centres and clinical units.
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Affiliation(s)
- G Prevot
- Service de pneumologie, clinique des voies respiratoires, hôpital Larrey, CHU Toulouse, Toulouse, France
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19
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Puthucheary Z, Skipworth JR, Rawal J, Loosemore M, Van Someren K, Montgomery HE. Genetic Influences in Sport and Physical Performance. Sports Med 2011; 41:845-59. [DOI: 10.2165/11593200-000000000-00000] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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20
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Ingebrigtsen TS, Thomsen SF, van der Sluis S, Miller M, Christensen K, Sigsgaard T, Backer V. Genetic influences on pulmonary function: a large sample twin study. Lung 2011; 189:323-30. [PMID: 21660583 DOI: 10.1007/s00408-011-9306-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2010] [Accepted: 05/26/2011] [Indexed: 10/18/2022]
Abstract
Heritability of forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), and peak expiratory flow (PEF) has not been previously addressed in large twin studies. We evaluated the genetic contribution to individual differences observed in FEV(1), FVC, and PEF using data from the largest population-based twin study on spirometry. Specially trained lay interviewers with previous experience in spirometric measurements tested 4,314 Danish twins (individuals), 46-68 years of age, in their homes using a hand-held spirometer, and their flow-volume curves were evaluated. Modern variance component sex-limitation models were applied to evaluate possible genetic differences between the sexes for FEV(1), FVC, and PEF. Estimates were adjusted for age, height, and smoking. For FEV(1), additive genetic effects of 61% (95% CI 56-65) were observed. For FVC, the additive genetic contribution was 26% (3-49%) and the dominant genetic contribution was 29% (4-54%). For PEF, our models showed an additive genetic contribution of 43% (31-52%) for men, but genetic influences were not significant in women. We found no significant differences between dizygotic same-sex twins and dizygotic opposite-sex twins for FEV(1), FVC, and PEF, suggesting absence of qualitative genetic differences between the sexes. Sex-difference heritability for PEF suggested possible quantitative genetic differences between the sexes for this index. Genetic effects contributed significantly to individual differences observed in FEV(1), FVC, and PEF. Qualitative sex differences were absent for all spirometric measures, while quantitative sex differences were observed only for PEF, with heritability being substantial in men but negligible in women.
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Affiliation(s)
- Truls S Ingebrigtsen
- Department of Respiratory Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400, Copenhagen, Denmark.
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21
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Abstract
The association of chronic obstructive pulmonary disease (COPD) and smoking is well established. However, an increasing number of studies have reported a not inconsiderable prevalence of COPD among nonsmokers. Therefore, other factors, both endogenous and exogenous, may influence the development of this disease. The present article reviews the influence of possible genetic factors, gender and other respiratory diseases (such as chronic asthma and tuberculosis), as well as environmental pollution and occupational exposure in the development of COPD.
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22
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Simon DM, Tsai LW, Ingenito EP, Starcher BC, Mariani TJ. PPARgamma deficiency results in reduced lung elastic recoil and abnormalities in airspace distribution. Respir Res 2010; 11:69. [PMID: 20525205 PMCID: PMC2889874 DOI: 10.1186/1465-9921-11-69] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2009] [Accepted: 06/02/2010] [Indexed: 11/11/2022] Open
Abstract
Background Peroxisome proliferator-activated receptor (PPAR)-γ is a nuclear hormone receptor that regulates gene expression, cell proliferation and differentiation. We previously described airway epithelial cell PPARγ deficient mice that develop airspace enlargement with decreased tissue resistance and increased lung volumes. We sought to understand the impact of airspace enlargement in conditionally targeted mice upon the physio-mechanical properties of the lung. Methods We measured elastic recoil and its determinants, including tissue structure and surface forces. We measured alveolar number using radial alveolar counts, and airspace sizes and their distribution using computer-assisted morphometry. Results Air vs. saline-filled pressure volume profiles demonstrated loss of lung elastic recoil in targeted mice that was contributed by both tissue components and surface tension, but was proportional to lung volume. There were no significant differences in surfactant quantity/function nor in elastin and collagen content between targeted animals and littermate controls. Importantly, radial alveolar counts were significantly reduced in the targeted animals and at 8 weeks of age there were 18% fewer alveoli with 32% more alveolar ducts. Additionally, the alveolar ducts were 19% larger in the targeted animals. Conclusions Our data suggest that the functional abnormalities, including loss of recoil are secondary to altered force transmission due to differences in the structure of alveolar ducts, rather than changes in surfactant function or elastin or collagen content. These data further define the nature of abnormal lung maturation in the absence of airway epithelial cell PPARγ and identify a putative genetic determinant of dysanapsis, which may serve as a precursor to chronic lung disease.
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Affiliation(s)
- Dawn M Simon
- Division of Respiratory Diseases, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
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23
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Mineo D, Ambrogi V, Cufari ME, Gambardella S, Pignotti L, Pompeo E, Mineo TC. Variations of inflammatory mediators and alpha1-antitrypsin levels after lung volume reduction surgery for emphysema. Am J Respir Crit Care Med 2010; 181:806-14. [PMID: 20056899 DOI: 10.1164/rccm.200910-1476oc] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE In emphysema, chronic inflammation, including protease-antiprotease imbalance, is responsible for declining pulmonary function and progressive cachexia. OBJECTIVES To evaluate variations of inflammatory mediators and alpha(1)-antitrypsin levels after lung volume reduction surgery (LVRS) compared with respiratory rehabilitation. METHODS A total of 28 patients with moderate to severe emphysema, who underwent video-assisted thoracoscopic LVRS, were compared with 26 similar patients, who refused operation and followed a standardized rehabilitation program, and to a matched healthy group. Respiratory function, body composition, circulating inflammatory mediators, and alpha(1)-antitrypsin levels were evaluated before and 12 months after treatment. Gene expression levels of inflammatory mediators and protease-antiprotease were assessed in emphysematous specimens from 17 operated patients by matching to normal tissue from resection margins. MEASUREMENTS AND MAIN RESULTS Significant improvements were only obtained after surgery in respiratory function (FEV(1), +25.2%, P < 0.0001; residual volume [RV], -19.5%, P < 0.0001; diffusing lung capacity for carbon monoxide, +3.3%, P < 0.05) and body composition (fat-free mass, +6.5%, P < 0.01; fat mass, +11.9%, P < 0.01), with decrement of circulating inflammatory mediators (TNF-alpha, -22.2%, P < 0.001; IL-6, -24.5%, P < 0.001; IL-8, -20.0%, P < 0.001) and increment of antiprotease levels (alpha(1)-antitrypsin, +27.0%, P < 0.001). Supportive gene expression analysis demonstrated active inflammation and protease hyperactivity in the resected emphysematous tissue. Reduction of TNF-alpha and IL-6 and increment of alpha(1)-antitrypsin levels significantly correlated with reduction of RV (P = 0.03, P = 0.009, and P = 0.001, respectively), and partially with increment of fat-free mass (P = 0.03, P = 0.02, and P = 0.09, respectively). CONCLUSIONS LVRS significantly reduced circulating inflammatory mediators and increased antiprotease levels over respiratory rehabilitation, also improving respiratory function and nutritional status. Correlations of inflammatory mediators and antiprotease levels with RV and, partly, with body composition suggest that elimination of inflammatory emphysematous tissue may explain clinical improvements after surgery.
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Affiliation(s)
- Davide Mineo
- Division of Thoracic Surgery, Tor Vergata University of Rome and Policlinic, 00133 Rome, Italy.
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Sharma S, Tantisira K, Carey V, Murphy AJ, Lasky-Su J, Celedón JC, Lazarus R, Klanderman B, Rogers A, Soto-Quirós M, Avila L, Mariani T, Gaedigk R, Leeder S, Torday J, Warburton D, Raby B, Weiss ST. A role for Wnt signaling genes in the pathogenesis of impaired lung function in asthma. Am J Respir Crit Care Med 2009; 181:328-36. [PMID: 19926868 DOI: 10.1164/rccm.200907-1009oc] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
RATIONALE Animal models demonstrate that aberrant gene expression in utero can result in abnormal pulmonary phenotypes. OBJECTIVES We sought to identify genes that are differentially expressed during in utero airway development and test the hypothesis that variants in these genes influence lung function in patients with asthma. METHODS Stage 1 (Gene Expression): Differential gene expression analysis across the pseudoglandular (n = 27) and canalicular (n = 9) stages of human lung development was performed using regularized t tests with multiple comparison adjustments. Stage 2 (Genetic Association): Genetic association analyses of lung function (FEV(1), FVC, and FEV(1)/FVC) for variants in five differentially expressed genes were conducted in 403 parent-child trios from the Childhood Asthma Management Program (CAMP). Associations were replicated in 583 parent-child trios from the Genetics of Asthma in Costa Rica study. MEASUREMENTS AND MAIN RESULTS Of the 1,776 differentially expressed genes between the pseudoglandular (gestational age: 7-16 wk) and the canalicular (gestational age: 17-26 wk) stages, we selected 5 genes in the Wnt pathway for association testing. Thirteen single nucleotide polymorphisms in three genes demonstrated association with lung function in CAMP (P < 0.05), and associations for two of these genes were replicated in the Costa Ricans: Wnt1-inducible signaling pathway protein 1 with FEV(1) (combined P = 0.0005) and FVC (combined P = 0.0004), and Wnt inhibitory factor 1 with FVC (combined P = 0.003) and FEV(1)/FVC (combined P = 0.003). CONCLUSIONS Wnt signaling genes are associated with impaired lung function in two childhood asthma cohorts. Furthermore, gene expression profiling of human fetal lung development can be used to identify genes implicated in the pathogenesis of lung function impairment in individuals with asthma.
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Affiliation(s)
- Sunita Sharma
- Channing Laboratory, Center for Genomic Medicine, 181 Longwood Avenue, Boston, MA 02115, USA.
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Sørheim IC, Gulsvik A, Bakke PS, Brøgger JC, Grydeland TB, Silverman EK. [Genetics in chronic obstructive pulmonary disease]. TIDSSKRIFT FOR DEN NORSKE LEGEFORENING 2009; 129:2104-7. [PMID: 19855448 DOI: 10.4045/tidsskr.09.0713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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Bossé Y. Genetics of chronic obstructive pulmonary disease: a succinct review, future avenues and prospective clinical applications. Pharmacogenomics 2009; 10:655-67. [PMID: 19374520 DOI: 10.2217/pgs.09.10] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is influenced by genetic and environmental factors. A large number of candidate gene-association studies and genome-wide linkage scans have been conducted to elucidate the genetic architecture underlying this disease. The compilation of these studies clearly revealed the complex genetic nature of COPD. Multiple genes acting on specific environmental backgrounds are likely to be the tenet of this multifactorial disorder. Encouragingly, reproducible susceptibility genes, such as SERPINE2, were recently identified. Advances in genomic research offer unprecedented capabilities to interrogate the human genome and are likely to accelerate the discovery of new genes. A comprehensive catalogue of genes implicated in the pathogenesis of COPD has great potential to lead to the development of new therapies and explain interindividual response to treatment.
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Affiliation(s)
- Yohan Bossé
- Institut universitaire de cardiologie et de pneumologie de Québec, Pavillon Margeritte-d'Youville, Y4190, 2725, Chemin Sainte-Foy, Quebec City, Quebec, G1V 4G5, Canada.
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Wilk JB, Chen TH, Gottlieb DJ, Walter RE, Nagle MW, Brandler BJ, Myers RH, Borecki IB, Silverman EK, Weiss ST, O'Connor GT. A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet 2009; 5:e1000429. [PMID: 19300500 PMCID: PMC2652834 DOI: 10.1371/journal.pgen.1000429] [Citation(s) in RCA: 248] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2008] [Accepted: 02/17/2009] [Indexed: 11/28/2022] Open
Abstract
The ratio of forced expiratory volume in one second to forced vital capacity (FEV(1)/FVC) is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV(1)/FVC ratio, analyzed as a percent of the predicted value. Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction. Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV(1)/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09). One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV(1)/FVC (p-value = 2.0e-04). The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV(1)/FVC ratio levels. Results from the Family Heart Study demonstrated that the association extended to FEV(1) and dichotomous airflow obstruction phenotypes, particularly among smokers. The SNP rs13147758 was associated with the percent predicted FEV(1)/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript. The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung. Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation.
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Affiliation(s)
- Jemma B Wilk
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
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Seibold MA, Wang B, Eng C, Kumar G, Beckman KB, Sen S, Choudhry S, Meade K, Lenoir M, Watson HG, Thyne S, Williams LK, Kumar R, Weiss KB, Grammer LC, Avila PC, Schleimer RP, Burchard EG, Brenner R. An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity. Hum Mol Genet 2008; 17:2681-90. [PMID: 18535015 PMCID: PMC2733805 DOI: 10.1093/hmg/ddn168] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2008] [Revised: 04/23/2008] [Accepted: 06/03/2008] [Indexed: 02/05/2023] Open
Abstract
A highly heritable and reproducible measure of asthma severity is baseline pulmonary function. Pulmonary function is largely determined by airway smooth muscle (ASM) tone and contractility. The large conductance, voltage and calcium-activated potassium (BK) channel negatively regulates smooth muscle tone and contraction in ASM. The modulatory subunit of BK channels, the beta1-subunit, is critical for proper activation of BK channels in smooth muscle and has shown sex hormone specific regulation. We hypothesized that KCNMB1 genetic variants in African Americans may underlie differences in bronchial smooth muscle tone and thus pulmonary function, possibly in a sex-specific manner. Through resequencing of the KCNMB1 gene we identified several common variants including a novel African-specific coding polymorphism (C818T, R140W). The C818T SNP and four other KCNMB1 variants were genotyped in two independent groups of African American asthmatics (n = 509) and tested for association with the pulmonary function measure--forced expiratory volume (FEV(1)) % of predicted value. The 818T allele is associated with a clinically significant decline (-13%) in FEV(1) in both cohorts of asthmatics among males but not females (P(combined) = 0.0003). Patch clamp electrophysiology studies of the BK channel expressed with the 140Trp variant of the beta1-subunit demonstrated significantly reduced channel openings, predicted by the loss of pulmonary function observed. African American male asthmatics carrying the 818T allele (10% of population) are potentially at risk for greater airway obstruction and increased asthma morbidity. Female asthmatics may be insulated from the deleterious effects of the 818T allele by estrogen-mediated upregulation in BK channel activity.
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Affiliation(s)
- Max A Seibold
- Department of Medicine, University of California San Francisco, San Francisco, CA 94143-2911, USA.
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Desai AA, Hysi P, Garcia JGN. Integrating genomic and clinical medicine: searching for susceptibility genes in complex lung diseases. Transl Res 2008; 151:181-93. [PMID: 18355765 PMCID: PMC3616408 DOI: 10.1016/j.trsl.2007.10.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2007] [Revised: 10/31/2007] [Accepted: 10/31/2007] [Indexed: 12/30/2022]
Abstract
The integration of molecular, genomic, and clinical medicine in the post-genome era provides the promise of novel information on genetic variation and pathophysiologic cascades. The current challenge is to translate these discoveries rapidly into viable biomarkers that identify susceptible populations and into the development of precisely targeted therapies. In this article, we describe the application of comparative genomics, microarray platforms, genetic epidemiology, statistical genetics, and bioinformatic approaches within examples of complex pulmonary pathobiology. Our search for candidate genes, which are gene variations that drive susceptibility to and severity of enigmatic acute and chronic lung disorders, provides a logical framework to understand better the evolution of genomic medicine. The dissection of the genetic basis of complex diseases and the development of highly individualized therapies remain lofty but achievable goals.
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Affiliation(s)
- Ankit A Desai
- Section of Pulmonary and Critical Care Medicine, Department of Medicine, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA
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30
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Abstract
Two views exist of medical science, says the author, one emphasizing discovery and explanation, the other emphasizing evaluation of interventions.
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Wilk JB, Walter RE, Laramie JM, Gottlieb DJ, O'Connor GT. Framingham Heart Study genome-wide association: results for pulmonary function measures. BMC MEDICAL GENETICS 2007; 8 Suppl 1:S8. [PMID: 17903307 PMCID: PMC1995616 DOI: 10.1186/1471-2350-8-s1-s8] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Pulmonary function measures obtained by spirometry are used to diagnose chronic obstructive pulmonary disease (COPD) and are highly heritable. We conducted genome-wide association (GWA) analyses (Affymetrix 100K SNP GeneChip) for measures of lung function in the Framingham Heart Study. METHODS Ten spirometry phenotypes including percent of predicted measures, mean spirometry measures over two examinations, and rates of change based on forced expiratory volume in one second (FEV1), forced vital capacity (FVC), forced expiratory flow from the 25th to 75th percentile (FEF25-75), the FEV1/FVC ratio, and the FEF25-75/FVC ratio were examined. Percent predicted phenotypes were created using each participant's latest exam with spirometry. Predicted lung function was estimated using models defined in the set of healthy never-smokers, and standardized residuals of percent predicted measures were created adjusting for smoking status, pack-years, and body mass index (BMI). All modeling was performed stratified by sex and cohort. Mean spirometry phenotypes were created using data from two examinations and adjusting for age, BMI, height, smoking and pack-years. Change in pulmonary function over time was studied using two to four examinations with spirometry to calculate slopes, which were then adjusted for age, height, smoking and pack-years. RESULTS Analyses were restricted to 70,987 autosomal SNPs with minor allele frequency > or = 10%, genotype call rate > or = 80%, and Hardy-Weinberg equilibrium p-value > or = 0.001. A SNP in the interleukin 6 receptor (IL6R) on chromosome 1 was among the best results for percent predicted FEF25-75. A non-synonymous coding SNP in glutathione S-transferase omega 2 (GSTO2) on chromosome 10 had top-ranked results studying the mean FEV1 and FVC measurements from two examinations. SNPs nearby the SOD3 and vitamin D binding protein genes, candidate genes for COPD, exhibited association to percent predicted phenotypes. CONCLUSION GSTO2 and IL6R are credible candidate genes for association to pulmonary function identified by GWA. These and other observed associations warrant replication studies. This resource of GWA results for pulmonary function measures is publicly available at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.
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Affiliation(s)
- Jemma B Wilk
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA
| | - Robert E Walter
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA
| | - Jason M Laramie
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA
- Program in Bioinformatics, Boston University, Boston, MA, USA
| | - Daniel J Gottlieb
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
| | - George T O'Connor
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA
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Ganguly K, Stoeger T, Wesselkamper SC, Reinhard C, Sartor MA, Medvedovic M, Tomlinson CR, Bolle I, Mason JM, Leikauf GD, Schulz H. Candidate genes controlling pulmonary function in mice: transcript profiling and predicted protein structure. Physiol Genomics 2007; 31:410-21. [PMID: 17804602 DOI: 10.1152/physiolgenomics.00260.2006] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Impaired development and reduced lung capacity are risk factors of asthma and chronic obstructive pulmonary disease. Previously, our genomewide linkage analysis of C3H/HeJ (C3H) and JF1/Msf (JF1) mouse strains identified quantitative trait loci (QTLs) associated with the complex traits of dead space volume (Vd), total lung capacity (TLC), lung compliance (CL), and diffusing capacity for CO (D(CO)). We assessed positional candidate genes by comparing C3H with JF1 lung transcript levels by microarray and by comparing C3H, BALB/cByJ, C57BL/6J, A/J, PWD/PhJ, and JF1 strains, using exon sequencing to predict protein structure. Microarray identified >900 transcripts differing in C3H and JF1 lungs related to lung development, function, and remodeling. Of these, three genes localized to QTLs associated with differences in lung function. C3H and JF1 strains differed in transcript and protein levels of superoxide dismutase 3, extracellular [SOD3; mouse chromosome (mCh) 5: VD] and transcript of trefoil factor 2 (TFF2; mCh 17: TLC and D(CO)), and ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2; mCh 15: TLC and CL). Nucleotide sequencing of Sod3, Tff2, and previously identified Relaxin 1 (Rln1; mCh 19: CL) uncovered polymorphisms that could lead to nonsynonymous amino acid changes and altered predicted protein structure. Gene-targeted Sod3(-/-) mice had increased conducting airway volume (Vd/TLC) compared with strain-matched control Sod3(+/+) mice, consistent with the QTL on mCh 5. Two novel genes (Tff2 and Enpp2) have been identified and two suspected genes (Sod3 and Rln1) have been supported as determinants of lung function in mice. Findings with gene-targeted mice suggest that SOD3 is a contributing factor defining the complex trait of conducting airway volume.
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Affiliation(s)
- Koustav Ganguly
- National Research Center for Environment and Health (GSF), Institute for Inhalation Biology, Neuherberg, Germany
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Raleigh SM, Davies BM, Cleal D, Ribbans WJ. No association between coding polymorphism within Exon 4 of the human surfactant protein B gene and pulmonary function in healthy men. J Physiol Sci 2007; 57:199-202. [PMID: 17540055 DOI: 10.2170/physiolsci.sc002607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2007] [Accepted: 05/29/2007] [Indexed: 11/05/2022]
Abstract
The coding polymorphism (rs1130866) within the surfactant protein B gene is known to associate with certain respiratory abnormalities. We investigated, using spirometry and fluorescence-based PCR, whether this variant influenced pulmonary function in healthy, nonsmoking men. We found no association of pulmonary function with genotype at the rs1130866 locus.
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Affiliation(s)
- Stuart M Raleigh
- The Biomedical Research Group, Division of Health and Life Sciences, The University of Northampton, UK.
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Wilk JB, Herbert A, Shoemaker CM, Gottlieb DJ, Karamohamed S. Secreted modular calcium-binding protein 2 haplotypes are associated with pulmonary function. Am J Respir Crit Care Med 2007; 175:554-60. [PMID: 17204727 PMCID: PMC1899283 DOI: 10.1164/rccm.200601-110oc] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
RATIONALE Previously reported linkage to FEV(1) (LOD score = 5.0) on 6q27 in the Framingham Heart Study (FHS) led us to explore a candidate gene, SMOC2, at 168.6 Mb. OBJECTIVES We tested association between SMOC2 polymorphisms and FEV(1) and FVC in unrelated FHS participants. METHODS Twenty single-nucleotide polymorphisms (SNPs) around SMOC2 were genotyped in 1,734 subjects. MEASUREMENTS AND MAIN RESULTS SNP data were analyzed using multiple linear regression models incorporating sex, age, body mass index, height, and smoking history as covariates, and analyses were repeated within strata of ever- and never-smokers. The minor allele of SNP rs1402 was associated with higher mean FEV(1) (p = 0.003) and FVC (p = 0.02) measures. In never-smoking subjects, association with higher measures was observed with the minor allele of rs747995 (FEV(1), p = 0.0006; FVC, p = 0.0008). These two SNPs lie in different haplotype blocks and reside in intron 4 of SMOC2. Haplotype analysis revealed a common G-T haplotype (rs747995-rs1402) with 77% frequency in never-smoking FHS subjects. The G-T haplotype was associated with reduction of 126 ml for FEV(1) (p = 0.0002) and 157 ml for FVC (p = 0.0002). The G-T haplotype was similarly associated in a set of never-smoking subjects from the Family Heart Study (FEV(1), p = 0.03; FVC, p = 0.03). CONCLUSIONS The replication of the association in two populations supports the possibility that SMOC2 might play an important role in the determination of FEV(1) and FVC.
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Affiliation(s)
- Jemma B Wilk
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
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Hersh CP, Soto-Quirós ME, Avila L, Lake SL, Liang C, Fournier E, Spesny M, Sylvia JS, Lazarus R, Hudson T, Verner A, Klanderman BJ, Freimer NB, Silverman EK, Celedón JC. Genome-wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica. Thorax 2006; 62:224-30. [PMID: 17099076 PMCID: PMC2117166 DOI: 10.1136/thx.2006.067934] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Although asthma is highly prevalent among certain Hispanic subgroups, genetic determinants of asthma and asthma-related traits have not been conclusively identified in Hispanic populations. A study was undertaken to identify genomic regions containing susceptibility loci for pulmonary function and bronchodilator responsiveness (BDR) in Costa Ricans. METHODS Eight extended pedigrees were ascertained through schoolchildren with asthma in the Central Valley of Costa Rica. Short tandem repeat (STR) markers were genotyped throughout the genome at an average spacing of 8.2 cM. Multipoint variance component linkage analyses of forced expiratory volume in 1 second (FEV(1)) and FEV(1)/ forced vital capacity (FVC; both pre-bronchodilator and post-bronchodilator) and BDR were performed in these eight families (pre-bronchodilator spirometry, n = 640; post-bronchodilator spirometry and BDR, n = 624). Nine additional STR markers were genotyped on chromosome 7. Secondary analyses were repeated after stratification by cigarette smoking. RESULTS Among all subjects, the highest logarithm of the odds of linkage (LOD) score for FEV(1) (post-bronchodilator) was found on chromosome 7q34-35 (LOD = 2.45, including the additional markers). The highest LOD scores for FEV(1)/FVC (pre-bronchodilator) and BDR were found on chromosomes 2q (LOD = 1.53) and 9p (LOD = 1.53), respectively. Among former and current smokers there was near-significant evidence of linkage to FEV(1)/FVC (post-bronchodilator) on chromosome 5p (LOD = 3.27) and suggestive evidence of linkage to FEV(1) on chromosomes 3q (pre-bronchodilator, LOD = 2.74) and 4q (post-bronchodilator, LOD = 2.66). CONCLUSIONS In eight families of children with asthma in Costa Rica, there is suggestive evidence of linkage to FEV(1) on chromosome 7q34-35. In these families, FEV(1)/FVC may be influenced by an interaction between cigarette smoking and a locus (loci) on chromosome 5p.
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Affiliation(s)
- Craig P Hersh
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA
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Young RP, Hopkins R, Black PN, Eddy C, Wu L, Gamble GD, Mills GD, Garrett JE, Eaton TE, Rees MI. Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function. Thorax 2006; 61:394-9. [PMID: 16467073 PMCID: PMC2111196 DOI: 10.1136/thx.2005.048512] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- R P Young
- Department of Medicine, University of Auckland, New Zealand
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Stolk J, Seersholm N, Kalsheker N. Alpha1-antitrypsin deficiency: current perspective on research, diagnosis, and management. Int J Chron Obstruct Pulmon Dis 2006; 1:151-60. [PMID: 18046892 PMCID: PMC2706616 DOI: 10.2147/copd.2006.1.2.151] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The Alpha One International Registry (AIR), a multinational research program focused on alpha1-antitrypsin (AAT) deficiency, was formed in response to a World Health Organization recommendation. Each of the nearly 20 participating countries maintains a national registry of patients with AAT deficiency and contributes to an international database located in Malmö, Sweden. This database is designed to increase understanding of AAT deficiency. Additionally, AIR members are engaged in active, wide-ranging investigations to improve the diagnosis, monitoring, and treatment of the disease and meet biennially to exchange views and research findings. The fourth biennial meeting was held in Copenhagen, Denmark, on 2-3 June 2005. This review covers the wide range of AAT deficiency-related topics that were addressed encompassing advances in genetic characterization, risk factor identification, clinical epidemiology, inflammatory and signalling processes, therapeutic advances, and lung imaging techniques.
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Affiliation(s)
- Jan Stolk
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
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Schwartz AG, Ruckdeschel JC. Familial lung cancer: genetic susceptibility and relationship to chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006; 173:16-22. [PMID: 16141445 PMCID: PMC2662980 DOI: 10.1164/rccm.200502-235pp] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Lung cancer continues to be the leading cause of cancer death, and although most lung cancer is attributable to cigarette smoking, underlying genetic susceptibility is suggested by studies demonstrating familial aggregation. The first family linkage study of lung cancer has identified linkage of lung, laryngeal, and pharyngeal cancer in families to a region on chromosome 6q23-25. Because lung cancer and chronic obstructive pulmonary disease (COPD) are known to aggregate in families beyond shared risk associated with smoking, the linkage results are compared and contrasted with results from genomewide linkage and association studies and candidate gene studies searching for genes for lung cancer, lung function, and COPD. Linkage on chromosome 6q to both lung cancer and lung function, and on 12 to lung cancer, COPD, and lung function, together with overlap in candidate genes for these outcomes, suggests that future research into underlying genetic mechanisms of lung disease would benefit from broadening the collection of family history data and better defining the "high risk" population. As familial risk of lung disease is better defined, referral into screening programs and prevention trials can be better targeted to reach families with both a history of lung cancer and COPD.
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Affiliation(s)
- Ann G Schwartz
- Karmanos Cancer Institute, 110 East Warren Avenue, Detroit, MI 48201, USA.
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Abstract
BACKGROUND Increasingly, molecular genetic techniques are being used to improve our understanding of a number of common late onset complex disorders, such as hypertension, Alzheimer's disease and noninsulin dependent diabetes mellitus. Molecular genetic approaches have the potential to yield new information about disease pathogenesis that may be of great importance for the development of future treatments. AIMS This review discusses the evidence for a genetic contribution to the development of chronic obstructive pulmonary disease (COPD) and specifically focuses on the hypothesis that asthma and COPD share some pathogenic mechanisms as originally proposed in 1960 in a theory that has since become known as the Dutch Hypothesis. In particular we will review the evidence from molecular genetics, both in support of and against the theory.
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Affiliation(s)
- C E Ruse
- Sheffield Institute for Studies on Ageing, University of Sheffield, Community Scienes Center, Northern Hospital, UK.
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40
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Ekosse G. General health status of residents of the Selebi Phikwe Ni-Cu mine area, Botswana. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2005; 15:373-81. [PMID: 16416754 DOI: 10.1080/09603120500155740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Residents of the Selebi Phikwe area, Botswana where nickel-copper (Ni-Cu) is being exploited often exhibit symptoms of varied degrees of ailments, sicknesses and diseases. A need to investigate their general health status was therefore eminent. Primary data was obtained by means of a questionnaire and structured interviews conducted with individuals, health service providers, business enterprises and educational Institutions. The generated data revealed common ailments, sicknesses and diseases in the area with the four most frequent health complaints being frequent coughing headaches, influenza/common colds and rampant chest pains. Research findings indicated that residents had respiratory tract-related problems, suspected to be linked to the effects of air pollution caused by the emission of sulphur dioxide (SO2) from mining and smelting activities. Residents were frequently in contact with SO2 and related gases and fumes, mineral and silica dust generated from the mining processes. No clearly demarcating differences were noticed in the health status of residents living in the control site from those in the main study area. However, sites most affected were those close to where Ni-Cu is exploited. Environmental factors resulting from mining and smelting activities, among others, could be contributory to the negative health effects occurring at Selebi Phikwe.
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Affiliation(s)
- Georges Ekosse
- X-Ray Diffraction Unit, Faculty of Science, University of Botswana, Gaborone, Botswana.
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Postma DS, Meyers DA, Jongepier H, Howard TD, Koppelman GH, Bleecker ER. Genomewide screen for pulmonary function in 200 families ascertained for asthma. Am J Respir Crit Care Med 2005; 172:446-52. [PMID: 15901612 PMCID: PMC2718527 DOI: 10.1164/rccm.200407-864oc] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2004] [Accepted: 05/15/2005] [Indexed: 11/16/2022] Open
Abstract
Changes in pulmonary function are important in determining asthma outcome. Genetic factors may influence airway obstruction in asthma. We performed a genomewide screen in 200 families of probands objectively diagnosed with asthma in the 1960s to identify chromosomal regions related to changes in pre- and postbronchodilator lung function (FEV1, VC, and FEV1%VC) and assess influences of early-life smoke exposure. Smoking (pack-years), age, sex, and height were covariates in variance component analyses. Significant evidence for linkage of pre- and postbronchodilator FEV1%VC was obtained for chromosome 2q32 (LOD,4.9, increasing to 6.03 with additional fine-mapping markers, and 3.2, respectively). Linkage existed for chromosome 5q for pre- and postbronchodilator VC (likelihood of disease [LOD], 1.8 and 2.6, respectively). Results for pre- and postbronchodilator FEV1 were less significant (LOD, 1.5 and 1.6, chromosomes 11p and 10q, respectively). Results were not affected by passive smoke exposure. There is significant evidence for linkage of FEV1%VC to chromosome 2q32 in families of probands with asthma, 35 cM proximal from linkage previously observed in families of probands with early-onset chronic obstructive pulmonary disease. Thus, there may be multiple genes on chromosome 2q that are important in determining presence and degree of airflow limitation in families ascertained for obstructive airway disease.
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Affiliation(s)
- Dirkje S Postma
- Department of Pulmonology, University Hospital, Hanzeplein 3, 9731 GZ Groningen, The Netherlands.
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Reinhard C, Meyer B, Fuchs H, Stoeger T, Eder G, Rüschendorf F, Heyder J, Nürnberg P, de Angelis MH, Schulz H. Genomewide Linkage Analysis Identifies Novel Genetic Loci for Lung Function in Mice. Am J Respir Crit Care Med 2005; 171:880-8. [PMID: 15640362 DOI: 10.1164/rccm.200409-1204oc] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE Pulmonary function, including lung volumes and compliance, may be genetically determined, but few genetic polymorphisms have been identified that control these traits. We used an experimental approach and performed the first whole genome scan for pulmonary function in mice. OBJECTIVES AND METHODS To identify novel chromosomal regions contributing to lung function, quantitative trait locus linkage analysis was applied in N(2) backcross and F(2) intercross mice derived from two inbred strains-C3H/HeJ and JF1/Msf-with extremely divergent phenotypes. MAIN RESULTS Significant linkages to total lung capacity with LOD (logarithm of the odds) scores up to 6.0 were detected on chromosomes 15 and 17, to dead space volume and lung compliance on chromosomes 5 and 15 (LOD scores higher than 4.0), to lung compliance also on chromosome 19 (LOD score of 5.8), and to diffusing capacity on chromosomes 15 and 17 (LOD scores up to 5.0). The region of interest on chromosome 17 near D17Mit133 contains a syntenic region to human chromosome 6q27, which was recently identified to be linked to lung function in humans. The identified intervals harbor valuable candidate genes, such as the relaxin1 and transforming growth factor beta receptor 3 gene, which revealed missense polymorphisms between the parental strains. CONCLUSION The study provides evidence for linkage of different measures of lung function on murine chromosomes 5, 15, 17, and 19 and suggests novel candidate genes that may also affect the expression of human pulmonary function.
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Bouzigon E, Dizier MH, Krähenbühl C, Lemainque A, Annesi-Maesano I, Betard C, Bousquet J, Charpin D, Gormand F, Guilloud-Bataille M, Just J, Le Moual N, Maccario J, Matran R, Neukirch F, Oryszczyn MP, Paty E, Pin I, Rosenberg-Bourgin M, Vervloet D, Kauffmann F, Lathrop M, Demenais F. Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families. Hum Mol Genet 2004; 13:3103-13. [PMID: 15509591 DOI: 10.1093/hmg/ddh340] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
A genome-wide scan for asthma phenotypes was conducted in the whole sample of 295 EGEA families selected through at least one asthmatic subject. In addition to asthma, seven phenotypes involved in the main asthma physiopathological pathways were considered: SPT (positive skin prick test response to at least one of 11 allergens), SPTQ score being the number of positive skin test responses to 11 allergens, Phadiatop (positive specific IgE response to a mixture of allergens), total IgE levels, eosinophils, bronchial responsiveness (BR) to methacholine challenge and %predicted FEV(1). Four regions showed evidence for linkage (P</=0.001): 6q14 for %FEV(1), 12p13 for IgE, 17q22-q24 for SPT and 21q21 for both SPTQ and %FEV(1). Nine other regions indicated smaller linkage signals (0.001<P</=0.005). While most of these regions have been reported by previous asthma and lung function screens, 6q14 appears to be a new region potentially linked to %FEV(1). To determine which of these various asthma phenotypes are more likely to share common genetic determinants, a principal component analysis was applied to the genome-wide LOD scores. This analysis revealed clustering of LODs for asthma, SPT and Phadiatop on one axis and clustering of LODs for %FEV(1), BR and SPTQ on the other, while LODs for IgE and eosinophils appeared to be independent from all other LODs. These results provide new insights into the potential sharing of genetic determinants by asthma-related phenotypes.
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DeMeo DL, Celedón JC, Lange C, Reilly JJ, Chapman HA, Sylvia JS, Speizer FE, Weiss ST, Silverman EK. Genome-wide linkage of forced mid-expiratory flow in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 170:1294-301. [PMID: 15347563 DOI: 10.1164/rccm.200404-524oc] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Familial aggregation of forced expiratory flow during the middle half of the FVC (FEF(25-75%)) and FEF(25-75%)/FVC has been observed in the Boston Early-Onset Chronic Obstructive Pulmonary Disease Study, but linkage results have not been reported for these phenotypes. An autosomal whole genome-wide linkage scan was performed in 72 pedigrees ascertained through a proband with severe, early-onset chronic obstructive pulmonary disease, and linkage analyses of FEF(25-75%) and FEF(25-75%)/FVC were performed using Sequential Oligogenic Linkage Analysis Routines. There was suggestive evidence for linkage of FEF(25-75%)/FVC with chromosome 2 (LOD 2.60 at 216 cM). In a smokers-only analysis, evidence for linkage was observed for postbronchodilator FEF(25-75%) with chromosome 12 (LOD 5.03 at 35 cM) and chromosomes 2 and 12 for FEF(25-75%)/FVC (LOD 4.12 at 221 cM and LOD 3.46 at 35 cM, respectively); in the smokers-only model, evidence for linkage also was robust for FEV(1)/FVC on chromosome 2 (LOD 4.13 at 229 cM) and FEV(1) on chromosome 12 (LOD 3.26 at 36 cM). Our analyses provide evidence for linkage of FEF(25-75%) and FEF(25-75%)/FVC on chromosomes 2q and 12p. LOD scores of greater than two were also observed for chromosomes 16, 20, and 22 with the smokers-only analysis, which may suggest gene-by-smoking interactions in these regions.
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Affiliation(s)
- Dawn L DeMeo
- Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
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Abstract
COPD is a complex mix of signs and symptoms in patients with chronic bronchitis and emphysema, diseases that largely result from cigarette smoking. Not all smokers, however, acquire COPD, and COPD can develop in nonsmokers. In the United States, COPD is currently the fourth leading cause of death. Surprisingly, there are no effective drug therapies for COPD that are able to significantly alter disease progression, and little is known of the underlying molecular mechanisms that are responsible for its occurrence. Candidate gene-association studies and linkage analyses have been reported for COPD patients. This review describes the genetic predisposition of healthy subjects or relatives of COPD patients to acquire COPD. In addition, the genetic bases of COPD with rapid decline of FEV1 are described, and the current genetic data that have been distilled from studies of COPD patients with a predominant emphysema phenotype, with chronic bronchitis phenotype, and with a response to bronchodilators are discussed.
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47
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DeMeo DL, Silverman EK. Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax 2004; 59:259-64. [PMID: 14985567 PMCID: PMC1746953 DOI: 10.1136/thx.2003.006502] [Citation(s) in RCA: 167] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
The genetic aspects of AAT deficiency and the variable manifestations of lung disease in PI Z individuals are reviewed. The role of modifying genetic factors which may interact with environmental factors (such as cigarette smoking) is discussed, and directions for future research are presented.
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Affiliation(s)
- D L DeMeo
- Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02446, USA.
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Wang D, Li X, Lin YC, Yang K, Guo X, Yang H. Power of linkage analysis using traits generated from simulated longitudinal data of the Framingham Heart Study. BMC Genet 2003; 4 Suppl 1:S28. [PMID: 14975096 PMCID: PMC1866463 DOI: 10.1186/1471-2156-4-s1-s28] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The Framingham Heart Study is a very successful longitudinal research for cardiovascular diseases. The completion of a 10-cM genome scan in Framingham families provided an opportunity to evaluate linkage using longitudinal data. Several descriptive traits based on simulated longitudinal data from the Genetic Analysis Workshop 13 (GAW13) were generated, and linkage analyses were performed for these traits. We compared the power of detecting linkage for baseline and slope genes in the simulated data of GAW13 using these traits. We found that using longitudinal traits based on multiple follow-ups may not be more powerful than using cross-sectional traits for genetic linkage analysis.
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Affiliation(s)
- Dai Wang
- Division of Medical Genetics, Medical Genetics Birth Defect Center, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California, 90048 USA
| | - Xiaohui Li
- Division of Medical Genetics, Medical Genetics Birth Defect Center, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California, 90048 USA
| | - Ying-Chao Lin
- Division of Medical Genetics, Medical Genetics Birth Defect Center, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California, 90048 USA
| | - Kai Yang
- Division of Medical Genetics, Medical Genetics Birth Defect Center, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California, 90048 USA
| | - Xiuqing Guo
- Division of Medical Genetics, Medical Genetics Birth Defect Center, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California, 90048 USA
- University of California, Los Angeles, California, 90095 USA
| | - Huiying Yang
- Division of Medical Genetics, Medical Genetics Birth Defect Center, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California, 90048 USA
- University of California, Los Angeles, California, 90095 USA
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Malhotra A, Peiffer AP, Ryujin DT, Elsner T, Kanner RE, Leppert MF, Hasstedt SJ. Further evidence for the role of genes on chromosome 2 and chromosome 5 in the inheritance of pulmonary function. Am J Respir Crit Care Med 2003; 168:556-61. [PMID: 12791583 DOI: 10.1164/rccm.200303-410oc] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
The spirometric measurements FEV1, FVC, and the ratio FEV1/FVC are used in the diagnosis of lung function disorders. Therefore, understanding the genetics underlying these spirometric measurements will increase our knowledge of the genetics of pulmonary function. FEV1 and FVC were measured on 264 members of 26 Utah Genetic Reference pedigrees, originally collected for the Centre d'Etude du Polymorphisme Humain genetic mapping project. Using segregation analysis, we inferred major locus inheritance of the FEV1/FVC ratio, although we could not distinguish between a dominant or recessive mode of inheritance. No evidence of major locus inheritance was found for either FEV1 or FVC. Suggestive evidence of linkage for the ratio FEV1/FVC was found on chromosome 2 (heterogeneity lod = 2.36, dominant model) and chromosome 5 (heterogeneity lod = 2.23, recessive model), replicating linkages from other studies. In addition, nonparametric variance component linkage analysis showed linkage of FEV1/FVC in both of these regions, providing further support to the results. No nonparametric lod scores over 1.5 were obtained for either FEV1 or FVC.
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Affiliation(s)
- Alka Malhotra
- University of Utah, Department of Human Genetics, 15 North 2030 East, Room 2100, Salt Lake City, UT 84112-5330, USA.
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Wilk JB, DeStefano AL, Arnett DK, Rich SS, Djousse L, Crapo RO, Leppert MF, Province MA, Cupples LA, Gottlieb DJ, Myers RH. A genome-wide scan of pulmonary function measures in the National Heart, Lung, and Blood Institute Family Heart Study. Am J Respir Crit Care Med 2003; 167:1528-33. [PMID: 12637344 DOI: 10.1164/rccm.200207-755oc] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Spirometric measures of pulmonary function exhibited high heritability in the National Heart, Lung, and Blood Institute Family Heart Study. A genome scan of FEV1, FVC, and the ratio of FEV1/FVC was performed to identify chromosomal regions influencing these measures. The pulmonary traits were adjusted through multiple linear regression techniques for the effects of age, age2, body mass index, height, smoking status, and pack-years of smoking. The distribution of FEV1/FVC was transformed to account for nonnormality, and standardized residuals were used as the quantitative trait for variance component linkage analysis in GENEHUNTER (Whitehead Institute, Cambridge, MA). The genome scan identified regions on chromosomes 4 and 18 with logarithm of the odds favoring linkage (LOD) scores above 2.5, and these two chromosomes were further evaluated by incorporating additional marker genotyping. The FEV1/FVC ratio was linked to chromosome 4 around 28 centimorgans (cM; D4S1511) with a LOD score of 3.5, and the transformed ratio was linked to the same region with a LOD of 2.0. FEV1 and FVC were suggestively linked to regions on chromosome 18 with multipoint LOD scores of 2.4 for FEV1 and 1.5 for FVC at 31 cM (D18S843) and a LOD of 2.9 for FVC at 79 cM (D18S858).
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Affiliation(s)
- Jemma B Wilk
- Boston University School of Medicine, B-601, 715 Albany Street, Boston, MA 02118, USA.
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