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).
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).
Authors: Nicola A Hanania; Hana Müllerova; Nicholas W Locantore; Jørgen Vestbo; Michael L Watkins; Emiel F M Wouters; Stephen I Rennard; Amir Sharafkhaneh Journal: Am J Respir Crit Care Med Date: 2010-10-01 Impact factor: 21.405
Authors: Jayaji M Moré; Dennis R Voelker; Lori J Silveira; Michael G Edwards; Edward D Chan; Russell P Bowler Journal: BMC Pulm Med Date: 2010-10-25 Impact factor: 3.317
Authors: J Vestbo; W Anderson; H O Coxson; C Crim; F Dawber; L Edwards; G Hagan; K Knobil; D A Lomas; W MacNee; E K Silverman; R Tal-Singer Journal: Eur Respir J Date: 2008-01-23 Impact factor: 16.671
Authors: Chunyu Liu; Franak Batliwalla; Wentian Li; Annette Lee; Ronenn Roubenoff; Evan Beckman; Houman Khalili; Aarti Damle; Marlena Kern; Richard Furie; Josée Dupuis; Robert M Plenge; Marieke J H Coenen; Timothy W Behrens; John P Carulli; Peter K Gregersen Journal: Mol Med Date: 2008 Sep-Oct Impact factor: 6.354
Authors: Craig P Hersh; Nadia N Hansel; Kathleen C Barnes; David A Lomas; Sreekumar G Pillai; Harvey O Coxson; Rasika A Mathias; Nicholas M Rafaels; Robert A Wise; John E Connett; Barbara J Klanderman; Francine L Jacobson; Ritu Gill; Augusto A Litonjua; David Sparrow; John J Reilly; Edwin K Silverman Journal: Am J Respir Cell Mol Biol Date: 2009-01-08 Impact factor: 6.914
Authors: Weiliang Qiu; Michael H Cho; John H Riley; Wayne H Anderson; Dave Singh; Per Bakke; Amund Gulsvik; Augusto A Litonjua; David A Lomas; James D Crapo; Terri H Beaty; Bartolome R Celli; Stephen Rennard; Ruth Tal-Singer; Steven M Fox; Edwin K Silverman; Craig P Hersh Journal: PLoS One Date: 2011-09-16 Impact factor: 3.240
Authors: Alvar Agustí; Lisa D Edwards; Stephen I Rennard; William MacNee; Ruth Tal-Singer; Bruce E Miller; Jørgen Vestbo; David A Lomas; Peter M A Calverley; Emiel Wouters; Courtney Crim; Julie C Yates; Edwin K Silverman; Harvey O Coxson; Per Bakke; Ruth J Mayer; Bartolome Celli Journal: PLoS One Date: 2012-05-18 Impact factor: 3.240
Authors: Wei Chen; John M Brehm; Ani Manichaikul; Michael H Cho; Nadia Boutaoui; Qi Yan; Kristin M Burkart; Paul L Enright; Jerome I Rotter; Hans Petersen; Shuguang Leng; Ma'en Obeidat; Yohan Bossé; Corry-Anke Brandsma; Ke Hao; Stephen S Rich; Rhea Powell; Lydiana Avila; Manuel Soto-Quiros; Edwin K Silverman; Yohannes Tesfaigzi; R Graham Barr; Juan C Celedón Journal: Ann Am Thorac Soc Date: 2015-03
Authors: Stefano Guerra; Marilyn Halonen; Monica M Vasquez; Amber Spangenberg; Debra A Stern; Wayne J Morgan; Anne L Wright; Iris Lavi; Lluïsa Tarès; Anne-Elie Carsin; Carlota Dobaño; Esther Barreiro; Jan-Paul Zock; Jesús Martínez-Moratalla; Isabel Urrutia; Jordi Sunyer; Dirk Keidel; Medea Imboden; Nicole Probst-Hensch; Jenny Hallberg; Erik Melén; Magnus Wickman; Jean Bousquet; Danielle C M Belgrave; Angela Simpson; Adnan Custovic; Josep M Antó; Fernando D Martinez Journal: Lancet Respir Med Date: 2015-07-06 Impact factor: 30.700
Authors: Xiangming Ji; Xinnan Niu; Jun Qian; Victoria Martucci; Sarah A Pendergrass; Ivan P Gorlov; Christopher I Amos; Joshua C Denny; Pierre P Massion; Melinda C Aldrich Journal: Am J Respir Cell Mol Biol Date: 2018-06 Impact factor: 6.914
Authors: Joshua M Galanter; Christopher R Gignoux; Dara G Torgerson; Lindsey A Roth; Celeste Eng; Sam S Oh; Elizabeth A Nguyen; Katherine A Drake; Scott Huntsman; Donglei Hu; Saunak Sen; Adam Davis; Harold J Farber; Pedro C Avila; Emerita Brigino-Buenaventura; Michael A LeNoir; Kelley Meade; Denise Serebrisky; Luisa N Borrell; William Rodríguez-Cintrón; Andres Moreno Estrada; Karla Sandoval Mendoza; Cheryl A Winkler; William Klitz; Isabelle Romieu; Stephanie J London; Frank Gilliland; Fernando Martinez; Carlos Bustamante; L Keoki Williams; Rajesh Kumar; José R Rodríguez-Santana; Esteban G Burchard Journal: J Allergy Clin Immunol Date: 2014-01-07 Impact factor: 10.793
Authors: John S House; Huiling Li; Laura M DeGraff; Gordon Flake; Darryl C Zeldin; Stephanie J London Journal: FASEB J Date: 2014-10-23 Impact factor: 5.191