Genetic Variants Associated with the Risk of Chronic Obstructive Pulmonary Disease with and without Lung Cancer

Chronic obstructive pulmonary disease (COPD) is a strong risk factor for lung cancer. Published studies about variations of genes encoding glutathione metabolism, DNA repair, and inflammatory response pathways in susceptibility to COPD were inconclusive. We evaluated 470 single-nucleotide polymorphisms (SNP) from 56 genes of these three pathways in 620 cases and 893 controls to identify susceptibility markers for COPD risk, using existing resources. We assessed SNP- and gene-level effects adjusting for sex, age, and smoking status. Differential genetic effects on disease risk with and without lung cancer were also assessed; cumulative risk models were established. Twenty-one SNPs were found to be significantly associated with risk of COPD (P < 0.01); gene-based analyses confirmed two genes (GCLC and GSS) and identified three additional genes (GSTO2, ERCC1, and RRM1). Carrying 12 high-risk alleles may increase risk by 2.7-fold; eight SNPs altered COPD risk without lung cancer by 3.1-fold and 4 SNPs altered the risk with lung cancer by 2.3-fold. Our findings indicate that multiple genetic variations in the three selected pathways contribute to COPD risk through GCLC, GSS, GSTO2, ERCC1, and RRM1 genes. Functional studies are needed to elucidate the mechanisms of these genes in the development of COPD, lung cancer, or both. Cancer Prev Res; 5(3); 365–73. ©2011 AACR.

[1]  Adam M. Gustafson,et al.  A chronic obstructive pulmonary disease related signature in squamous cell lung cancer. , 2011, Lung cancer.

[2]  G. Lefranc,et al.  Correlation of EPHX1, GSTP1, GSTM1, and GSTT1 genetic polymorphisms with antioxidative stress markers in chronic obstructive pulmonary disease , 2011, Experimental lung research.

[3]  E. Duhig,et al.  Common pathogenic mechanisms and pathways in the development of COPD and lung cancer , 2011, Expert opinion on therapeutic targets.

[4]  C. Rooney,et al.  The Epithelial Cell and Lung Cancer: The Link between Chronic Obstructive Pulmonary Disease and Lung Cancer , 2011, Respiration.

[5]  S. Mandrekar,et al.  Alpha1-Antitrypsin Deficiency Carriers, Serum Alpha 1-Antitrypsin Concentration, and Non-small Cell Lung Cancer Survival , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[6]  G. Gamble,et al.  Chromosome 4q31 locus in COPD is also associated with lung cancer , 2010, European Respiratory Journal.

[7]  F. Jiang,et al.  A Panel of Sputum-Based Genomic Marker for Early Detection of Lung Cancer , 2010, Cancer Prevention Research.

[8]  William Wheeler,et al.  Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD , 2010, PLoS genetics.

[9]  I. Rahman,et al.  CYP1A1, CYP1A2 and CYBA gene polymorphisms associated with oxidative stress in COPD. , 2010, Clinica chimica acta; international journal of clinical chemistry.

[10]  Zhifu Sun,et al.  Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. , 2010, The Lancet. Oncology.

[11]  H. Hisatomi,et al.  Alternative RNA splicing in expression of the glutathione synthetase gene in human cells , 2010, Molecular Biology Reports.

[12]  Christoph Lange,et al.  Variants in FAM13A are associated with chronic obstructive pulmonary disease , 2010, Nature Genetics.

[13]  J. Cunningham,et al.  A Rigorous and Comprehensive Validation: Common Genetic Variations and Lung Cancer , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[14]  James J. Yang.  Distribution of Fisher's combination statistic when the tests are dependent , 2010 .

[15]  P. Black,et al.  A gene-based risk score for lung cancer susceptibility in smokers and ex-smokers , 2009, Postgraduate Medical Journal.

[16]  Zhen-xiang Zhang,et al.  hOGG1 Ser326Cys and XRCC1 Arg399Gln polymorphisms associated with chronic obstructive pulmonary disease. , 2009, Chinese medical journal.

[17]  E. Szabo,et al.  Lung cancer and chronic obstructive pulmonary disease: needs and opportunities for integrated research. , 2009, Journal of the National Cancer Institute.

[18]  K. Shianna,et al.  A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci , 2009, PLoS genetics.

[19]  P. Metcalf,et al.  COPD prevalence is increased in lung cancer, independent of age, sex and smoking history , 2009, European Respiratory Journal.

[20]  E. Wouters,et al.  Association of glutathione-S-transferase omega haplotypes with susceptibility to chronic obstructive pulmonary disease , 2009, Free radical research.

[21]  R. Laniado-Laborín.  Smoking and Chronic Obstructive Pulmonary Disease (COPD). Parallel Epidemics of the 21st Century , 2009, International journal of environmental research and public health.

[22]  Simon Heath,et al.  Lung cancer susceptibility locus at 5p15.33 , 2008, Nature Genetics.

[23]  G. Gamble,et al.  Lung cancer gene associated with COPD: triple whammy or possible confounding effect? , 2008, European Respiratory Journal.

[24]  John Whittaker,et al.  Analysis of multiple SNPs in a candidate gene or region , 2008, Genetic epidemiology.

[25]  S. Chanock,et al.  A report of cytokine polymorphisms and COPD risk in Xuan Wei, China. , 2008, International journal of hygiene and environmental health.

[26]  Cleo C. van Diemen,et al.  Lung function loss, smoking, vitamin C intake, and polymorphisms of the glutamate-cysteine ligase genes. , 2008, American journal of respiratory and critical care medicine.

[27]  C. Winkelman,et al.  Genetic influences in common respiratory disorders. , 2008, Critical care nursing clinics of North America.

[28]  W. Bamlet,et al.  Alpha1-antitrypsin deficiency carriers, tobacco smoke, chronic obstructive pulmonary disease, and lung cancer risk. , 2008, Archives of internal medicine.

[29]  G. Mills,et al.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 , 2008, Nature Genetics.

[30]  Paolo Vineis,et al.  A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 , 2008, Nature.

[31]  R. Tkacova,et al.  Glutathione S-transferase and microsomal epoxide hydrolase gene polymorphisms and risk of chronic obstructive pulmonary disease in Slovak population. , 2008, Croatian medical journal.

[32]  N. Zhong,et al.  Suppression of Oxidant-Induced Glutathione Synthesis by Erythromycin in Human Bronchial Epithelial Cells , 2007, Respiration.

[33]  Wendy Czika,et al.  Combining p‐values in large‐scale genomics experiments , 2007, Pharmaceutical statistics.

[34]  D. Au,et al.  Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. , 2007, American journal of respiratory and critical care medicine.

[35]  G. Scagliotti,et al.  ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[36]  Avrum Spira,et al.  State of the art. Chronic obstructive pulmonary disease, inflammation, and lung cancer. , 2006, Proceedings of the American Thoracic Society.

[37]  R. Weinshilboum,et al.  Role of the glutathione metabolic pathway in lung cancer treatment and prognosis: a review. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  N. Siafakas,et al.  Microsatellite DNA instability in benign lung diseases. , 2006, Respiratory medicine.

[39]  E. Wouters,et al.  Systemic Inflammation in COPD: Is Genetic Susceptibility a Key Factor? , 2006, COPD.

[40]  J. Hoeijmakers,et al.  The Structure-Specific Endonuclease Ercc1-Xpf Is Required To Resolve DNA Interstrand Cross-Link-Induced Double-Strand Breaks , 2004, Molecular and Cellular Biology.

[41]  W. MacNee,et al.  Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper , 2004, European Respiratory Journal.

[42]  G. Bepler,et al.  RRM1-induced metastasis suppression through PTEN-regulated pathways , 2003, Oncogene.

[43]  S. Guerra,et al.  How accurate is the self-reported diagnosis of chronic bronchitis? , 2002, Chest.

[44]  E. Silverman,et al.  Chronic obstructive pulmonary disease • 1: Susceptibility factors for COPD the genotype–environment interaction , 2002, Thorax.

[45]  Claude Deschamps,et al.  Polymorphisms in the promoter region of the neutrophil elastase gene are associated with lung cancer development. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[46]  E. Silverman.  Genetic Epidemiology of COPD. , 2002, Chest.

[47]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[48]  W. MacNee,et al.  Localization of gamma-glutamylcysteine synthetase messenger rna expression in lungs of smokers and patients with chronic obstructive pulmonary disease. , 2000, Free radical biology & medicine.

[49]  C. Rochester,et al.  Smoking and chronic obstructive pulmonary disease. , 2000, Clinics in chest medicine.

[50]  W. MacNee,et al.  Induction of γ‐glutamylcysteine synthetase by cigarette smoke is associated with AP‐1 in human alveolar epithelial cells , 1996 .

[51]  A. Miller,et al.  Lung function testing: selection of reference values and interpretative strategies. , 1992, The American review of respiratory disease.

[52]  S. Redline,et al.  Genotypic and phenotypic similarities in pulmonary function among family members of adult monozygotic and dizygotic twins. , 1989, American journal of epidemiology.

[53]  Ja.  Chronic Obstructive Pulmonary Disease , 1986 .

[54]  A. Sastre,et al.  Alpha 1-antitrypsin Pi-types in 965 COPD patients. , 1986, Chest.

[55]  Momiao Xiong,et al.  Gene and pathway-based second-wave analysis of genome-wide association studies , 2010, European Journal of Human Genetics.

[56]  A. Hofman,et al.  Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function , 2010, Nature Genetics.

[57]  W. Bamlet,et al.  Alpha 1-Antitrypsin Deficiency Carriers , Tobacco Smoke , Chronic Obstructive Pulmonary Disease , and Lung Cancer Risk , 2008 .

[58]  J. Brody,et al.  Chronic obstructive pulmonary disease, inflammation, and lung cancer , 2006 .

[59]  N. Tetlow,et al.  Characterization of the omega class of glutathione transferases. , 2005, Methods in enzymology.

[60]  D. Postma,et al.  Chronic obstructive pulmonary disease. , 2002, Clinical evidence.

[61]  W. MacNee,et al.  Induction of gamma-glutamylcysteine synthetase by cigarette smoke is associated with AP-1 in human alveolar epithelial cells. , 1996, FEBS letters.

[62]  Lung function testing: selection of reference values and interpretative strategies. American Thoracic Society. , 1991, The American review of respiratory disease.