title: Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD.
abstract: Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10-10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.
authors.affiliation: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kechris
authors.affiliation: National Jewish Health, Denver, Colorado, United States of America.
authors.forename: Sean
authors.identifier: http://orcid.org/0000-0001-9937-419X
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authors.lastname: Jacobson
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: M Bradley
authors.initials: MB
authors.lastname: Drummond
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hawkins
authors.affiliation: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Jenny
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Ting-Huei
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Collaborative Studies Coordinating Center, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Pedro Miguel
authors.initials: PM
authors.lastname: Quibrera
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina United States of America.
authors.forename: Wayne
authors.initials: W
authors.lastname: Anderson
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York; Department of Epidemiology, Mailman School of Public Health at Columbia University, New York, New York, United States of America.
authors.forename: R Graham
authors.initials: RG
authors.lastname: Barr
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Patricia V
authors.identifier: http://orcid.org/0000-0002-4704-2414
authors.initials: PV
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authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
authors.affiliation: Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University,Baltimore, Maryland, United States of America.
authors.forename: Terri
authors.initials: T
authors.lastname: Beaty
authors.affiliation: Division of Respiratory and Critical Care Physiology and Medicine, Harbor- University of California at Los Angeles Medical Center, Torrance, California, United States of America.
authors.forename: Richard
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authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
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authors.lastname: Castaldi
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Comellas
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado, United States of America.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Gerard
authors.initials: G
authors.lastname: Criner
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Dawn
authors.initials: D
authors.lastname: Demeo
authors.affiliation: Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of San Francisco Medical Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Christenson
authors.affiliation: Collaborative Studies Coordinating Center, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Couper
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan; VA Ann Arbor Healthcare System, Ann Arbor, Michigan, United States of America.
authors.forename: Jeffrey L
authors.identifier: http://orcid.org/0000-0001-5191-4847
authors.initials: JL
authors.lastname: Curtis
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina United States of America.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Doerschuk
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan; VA Ann Arbor Healthcare System, Ann Arbor, Michigan, United States of America.
authors.forename: Christine M
authors.initials: CM
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authors.affiliation: Collaborative Studies Coordinating Center, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Gouskova
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
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authors.initials: MK
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authors.affiliation: Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
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authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Nadia N
authors.initials: NN
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authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
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authors.initials: CP
authors.lastname: Hersh
authors.affiliation: Department of Radiology, Division of Physiologic Imaging, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hoffman
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kaner
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Richard E
authors.initials: RE
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authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
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authors.initials: EC
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authors.affiliation: Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lutz
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, New York, United States of America.
authors.forename: Fernando J
authors.initials: FJ
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authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Meyers
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Immunologic Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Peters
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado United States of America.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Regan
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Nebraska, Omaha, Nebraska, United States of America.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Scholand
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Edwin K
authors.initials: EK
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authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco School of Medicine, San Francisco, California, United States of America.
authors.forename: Prescott G
authors.initials: PG
authors.lastname: Woodruff
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina United States of America.
authors.forename: Wanda K
authors.initials: WK
authors.lastname: O'Neal
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mesh_terms: D000017:ABO Blood-Group System / Q000235:genetics; D015415:Biomarkers / Q000097:blood*; D001798:Blood Proteins / Q000235:genetics*; D004646:Emphysema / Q000097:blood / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000235:genetics* / Q000473:pathology; D040641:Quantitative Trait Loci / Q000235:genetics
chemical_list: D000017:ABO Blood-Group System; D015415:Biomarkers; D001798:Blood Proteins