Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD
Creators: name: Adams, Sandra
name: Swift, Irene
name: El-Bouiez, Adel
name: Weissfeld, Joel
name: Guy, Elizabeth
name: Mann, Tanya
name: Qiao, Dandi
name: Maselli-Caceres, Diego
name: Hokanson, John E.
name: McEvoy, Charlene
name: LaVange, Lisa M.
name: O’Neal, Wanda K.
name: Ruiz, Mario E.
name: Kanner, Richard E.
name: Ross, James C
name: Jacobson, Francine
name: Tschirren, Juerg
name: Fuhrman, Carl
name: Thompson, Brad
name: Kelsen, Steven
name: Chen, Ting-Huei
name: Humphries, Stephen
name: Bell, Brian
name: Al Qaisi, Mustafa
name: Jacobs, Michael
name: San Jose Estepar, Raul
name: Bowler, Russell
name: Dransfield, Mark
name: Alexis, Neil E.
name: Cho, Michael
name: Newell, John
name: Crapo, James
name: Wilson, Carla
name: Curtis, Jeffrey L.
name: Tashjian, Joseph
name: Rosiello, Richard
name: Rossiter, Harry
name: Swift, Alex
name: Washko, George
name: Peters, Stephen P.
name: Fischer, Hans
name: Hardin, Megan
name: Stinson, Douglas
name: Adami, Alessandra
name: Lazarus, Stephen C.
name: Cooper, Christopher B.
name: Duca, Lindsey
name: Berkowitz, Eugene
name: Bowler, Russell
name: Han, MeiLan K.
name: Busch, Robert
name: Hoffman, Eric A.
name: Anzueto, Antonio
name: Ciccolella, David
name: Han, MeiLan
name: Hansel, Nadia
name: Washington, Lacey
name: Castaldi, Peter
name: Desai, Parag
name: Wise, Robert A.
name: Begum, Ferdouse
name: Parulekar, Amit
name: Sun, Wei
name: Cho, Michael H.
name: Budoff, Matthew
name: Beaty, Terri
name: Strand, Matt
name: Kluiber, Alex
name: Judy, Philip F
name: Bailey, William
name: Soler, Xavier
name: Dransfield, Mark T.
name: Regan, Elizabeth
name: Carretta, Elizabeth E.
name: Parker, Margaret
name: Lynch, David A.
name: Bhatt, Surya
name: Friedman, Paul
name: Everett, Douglas
name: Hawkins, Gregory A.
name: Kechris, Katerina
name: Sieren, Jered
name: Lutz, Sharon
name: Sciurba, Frank
name: Wise, Robert
name: Hersh, Craig P.
name: Schroeder, Joyce
name: Chandra, Divay
name: Kazerooni, Ella A
name: Wendt, Christine
name: Won, Sungho
name: Nachiappan, Arun
name: Stoel, Berend C
name: Bandi, Venkata
name: Hanania, Nicola A.
name: Dass, Chandra
name: Horton, Karen
name: Wan, Emily
name: James Mamary, 
name: Paine, Robert
name: Pace, David
name: Freeman, Christine M.
name: Brown, Robert
name: Newell, John D.
name: McDonald, Merry-Lynn
name: Boucher, Richard C.
name: Alapat, Philip
name: Pratte, Katherine
name: Bon, Jessica
name: Vega-Sanchez, Maria Elena
name: Steiner, Robert M.
name: Austin, John
name: Martinez, Carlos H.
name: Nath, Hrudaya
name: Allen, Tadashi
name: Yang, Jenny
name: Billings, Joanne
name: Kleerup, Eric C.
name: van Ginneken, Bram
name: Lan, Charlie
name: D'Souza, Belinda
name: Atik, Mustafa
name: Hobbs, Brian
name: Michael Wells, 
name: Woodruff, Prescott G.
name: Pearson, Gregory D.N.
name: Comellas, Alejandro
name: Faino, Anna
name: Halper-Stromberg, Eitan
name: Laird, Nan
name: Sharafkhaneh, Amir
name: Drummond, M. Bradley
name: Thomashow, Byron
name: Comellas, Alejandro P.
name: Foreman, Marilyn
name: Hersh, Craig
name: D'Alonzo, Gilbert
name: Criner, Gerard
name: Cornellas, Alejandro
name: Meyers, Deborah A.
name: Jensen, Robert
name: Couper, David J.
name: Silverman, Edwin K.
name: McAdams, H. Page
name: Kazerooni, Ella
name: Jacobson, Francine L
name: Martinez, Carlos
name: Casaburi, Richard
name: Silverman, Edwin
name: Kim, Victor
name: Shenoy, Kartik
name: Yen, Andrew
name: Putcha, Nirupama
name: Doerschuk, Claire M.
name: Demeo, Dawn
name: Gray, Teresa
name: MacIntyre, Neil
name: Crapo, James D.
name: Lynch, David
name: Bleecker, Eugene R.
name: Satti, Aditi
name: Barr, R. Graham
name: Gouskova, Natalia A.
name: Boriek, Aladin
name: Oelsner, Elizabeth C.
name: Tashkin, Donald P.
name: Crystal, Ronald G.
name: Wilson, Carla G
name: Kaner, Robert J.
name: Jacobson, Sean
name: Regan, Elizabeth A.
name: De, Dawn
name: Santorico, Stephanie
name: Hastie, Annette T.
name: Van Beek, Edwin
name: Kinney, Gregory
name: Rennard, Stephen I.
name: Scholand, Mary Beth
name: Martinez, Fernando J.
name: Hokanson, John
name: Coxson, Harvey O.
name: Marchetti, Nathaniel
name: Ramsdell, Joe
name: Quibrera, Pedro Miguel
name: Lange, Christoph
name: Pernicano, Perry G.
name: van Rikxoort, Eva
name: Young, Kendra
name: Anderson, Wayne
name: Hansel, Nadia N.
name: Wells, J. Michael
name: Hetmanski, Jacqueline
name: Criner, Gerard J.
name: Porszasz, Janos
name: Rozenshtein, Anna
name: Christenson, Stephanie A.
name: Krishnan, Jerry A.
name: Westney, Gloria
name: Lutz, Sharon
name: Make, Barry
name: Guntupalli, Kalpatha
name: Basta, Patricia V.
name: Cordova, Francis
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2016

description: 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.