Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease.

RATIONALE A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. OBJECTIVES To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD. METHODS GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10(-8)), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated. MEASUREMENTS AND MAIN RESULTS Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009-0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001-0.049), although these COPD associations were not replicated in two additional cohorts. CONCLUSIONS Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

[1]  P. Monaci,et al.  Synergistic trans‐activation of the human C‐reactive protein promoter by transcription factor HNF‐1 binding at two distinct sites. , 1990, The EMBO journal.

[2]  S. Steinberg,et al.  Clara cell 10 kDa protein mRNA in normal and atypical regions of human respiratory epithelium , 1994, International journal of cancer.

[3]  P. Burton,et al.  Association between plasma CC16 levels, the A38G polymorphism, and asthma. , 2000, American journal of respiratory and critical care medicine.

[4]  C. Hermans,et al.  Clara Cell Secretory Protein (CC16): Features as a Peripheral Lung Biomarker , 2000, Annals of the New York Academy of Sciences.

[5]  R. Pauwels,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. , 2001, American journal of respiratory and critical care medicine.

[6]  B. Ghosh,et al.  Association of an intragenic microsatellite marker in the CC16 gene with asthma in the Indian population , 2004, Journal of Human Genetics.

[7]  A. Jemal,et al.  Trends in the leading causes of death in the United States, 1970-2002. , 2005, JAMA.

[8]  P. Ridker,et al.  Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)--can C-reactive protein be used to target statin therapy in primary prevention? , 2006, The American journal of cardiology.

[9]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[10]  T. Sørensen,et al.  Surfactant Protein D of the Innate Immune Defence is Inversely Associated with Human Obesity and SP‐D Deficiency Infers Increased Body Weight in Mice , 2006, Scandinavian journal of immunology.

[11]  G. Canonica,et al.  Clara cell 16 protein in COPD sputum: a marker of small airways damage? , 2007, Respiratory medicine.

[12]  E. Silverman,et al.  The SERPINE2 gene is associated with chronic obstructive pulmonary disease. , 2006, American Journal of Human Genetics.

[13]  A. Agustí.  Systemic effects of chronic obstructive pulmonary disease: what we know and what we don't know (but should). , 2007, Proceedings of the American Thoracic Society.

[14]  W. MacNee,et al.  Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) , 2008, European Respiratory Journal.

[15]  Jacques Fellay,et al.  WGAViewer: software for genomic annotation of whole genome association studies. , 2008, Genome research.

[16]  Wentian Li,et al.  Genome-Wide Association Scan Identifies Candidate Polymorphisms Associated with Differential Response to Anti-TNF Treatment in Rheumatoid Arthritis , 2008, Molecular medicine.

[17]  Børge G Nordestgaard,et al.  Genetically elevated C-reactive protein and ischemic vascular disease. , 2008, The New England journal of medicine.

[18]  J. Dreiher,et al.  Psoriasis and chronic obstructive pulmonary disease: a case–control study , 2008, The British journal of dermatology.

[19]  M. Rieder,et al.  Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. , 2008, American journal of human genetics.

[20]  L. Edwards,et al.  Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort , 2008, Thorax.

[21]  F. Karadağ,et al.  Biomarkers of Systemic Inflammation in Stable and Exacerbation Phases of COPD , 2008, Lung.

[22]  E. Boerwinkle,et al.  Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout , 2009, Proceedings of the National Academy of Sciences.

[23]  P. Paré,et al.  Associations of IL6 polymorphisms with lung function decline and COPD , 2009, Thorax.

[24]  C. Carlson,et al.  Common Coding Variants of the HNF1A Gene Are Associated With Multiple Cardiovascular Risk Phenotypes in Community-Based Samples of Younger and Older European-American Adults: The Coronary Artery Risk Development in Young Adults Study and The Cardiovascular Health Study , 2009, Circulation. Cardiovascular genetics.

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

[26]  David C. Wilson,et al.  Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn Disease. , 2009, American journal of human genetics.

[27]  C. Gieger,et al.  Association of Novel Genetic Loci With Circulating Fibrinogen Levels: A Genome-Wide Association Study in 6 Population-Based Cohorts , 2009, Circulation. Cardiovascular genetics.

[28]  L. Edwards,et al.  Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD , 2009, European Respiratory Journal.

[29]  Edwin K Silverman,et al.  Transforming growth factor-beta receptor-3 is associated with pulmonary emphysema. , 2009, American journal of respiratory cell and molecular biology.

[30]  W. Naumnik,et al.  Concentration of surfactant protein D, Clara cell protein CC-16 and IL-10 in bronchoalveolar lavage (BAL) in patients with sarcoidosis, hypersensivity pneumonitis and idiopathic pulmonary fibrosis. , 2009, Folia histochemica et cytobiologica.

[31]  Ruth Tal-Singer,et al.  Sputum neutrophils as a biomarker in COPD: findings from the ECLIPSE study , 2010, Respiratory research.

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

[33]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[34]  J. Soriano,et al.  Systemic inflammation in chronic obstructive pulmonary disease: a population-based study , 2010, Respiratory research.

[35]  E. Regan,et al.  Genetic Epidemiology of COPD (COPDGene) Study Design , 2011, COPD.

[36]  R. Bowler,et al.  Smoking reduces surfactant protein D and phospholipids in patients with and without chronic obstructive pulmonary disease , 2010, BMC pulmonary medicine.

[37]  H. Coon,et al.  Multistudy fine mapping of chromosome 2q identifies XRCC5 as a chronic obstructive pulmonary disease susceptibility gene. , 2010, American journal of respiratory and critical care medicine.

[38]  J. Danesh,et al.  Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies , 2010, The Lancet.

[39]  V. Salomaa,et al.  C-reactive protein-associated genetic variants and cancer risk: findings from FINRISK 1992, FINRISK 1997 and Health 2000 studies. , 2011, European journal of cancer.

[40]  E. Silverman,et al.  Polymorphisms in surfactant protein-D are associated with chronic obstructive pulmonary disease. , 2011, American journal of respiratory cell and molecular biology.

[41]  N. Sattar,et al.  Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses , 2011, BMC Medical Genetics.

[42]  Fred A. Wright,et al.  Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2 , 2011, Nature Genetics.

[43]  Taesung Park,et al.  Large-scale genome-wide association studies in east Asians identify new genetic loci influencing metabolic traits , 2011, Nature Genetics.

[44]  Bartolome Celli,et al.  Induced sputum genes associated with spirometric and radiological disease severity in COPD ex-smokers , 2011, Thorax.

[45]  M. Elmlinger,et al.  Comprehensive characterisation of pulmonary and serum surfactant protein D in COPD , 2011, Respiratory research.

[46]  J. Vestbo,et al.  Determinants of depression in the ECLIPSE chronic obstructive pulmonary disease cohort. , 2011, American journal of respiratory and critical care medicine.

[47]  T. Beaty,et al.  Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease , 2011, PloS one.

[48]  C. Gieger,et al.  A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. , 2011, Human molecular genetics.

[49]  H. Lin,et al.  Association between psoriasis and chronic obstructive pulmonary disease: a population‐based study in Taiwan , 2012, Journal of the European Academy of Dermatology and Venereology : JEADV.

[50]  L. Edwards,et al.  Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. , 2012, American journal of respiratory and critical care medicine.

[51]  L. Edwards,et al.  A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. , 2012, Human molecular genetics.

[52]  Courtney Crim,et al.  Persistent Systemic Inflammation is Associated with Poor Clinical Outcomes in COPD: A Novel Phenotype , 2012, PloS one.

[53]  F. Martinez,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. , 2007, American journal of respiratory and critical care medicine.