Document Detail


Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility.
MedLine Citation:
PMID:  23299987     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30% of the total effect of variants in the AGPHD1/CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly (r (2) = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42%) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking.
Authors:
Mateusz Siedlinski; Dustin Tingley; Peter J Lipman; Michael H Cho; Augusto A Litonjua; David Sparrow; Per Bakke; Amund Gulsvik; David A Lomas; Wayne Anderson; Xiangyang Kong; Stephen I Rennard; Terri H Beaty; John E Hokanson; James D Crapo; Christoph Lange; Edwin K Silverman;
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Publication Detail:
Type:  Clinical Trial; Journal Article; Multicenter Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.     Date:  2013-01-09
Journal Detail:
Title:  Human genetics     Volume:  132     ISSN:  1432-1203     ISO Abbreviation:  Hum. Genet.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-05-02     Revised Date:  2014-04-29    
Medline Journal Info:
Nlm Unique ID:  7613873     Medline TA:  Hum Genet     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  431-41     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aged
Carrier Proteins / genetics
Case-Control Studies
Female
GTPase-Activating Proteins / genetics
Genetic Loci*
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Iron Regulatory Protein 2 / genetics
Male
Membrane Glycoproteins / genetics
Middle Aged
Multigene Family*
Polymorphism, Single Nucleotide*
Pulmonary Disease, Chronic Obstructive / genetics*
Receptors, Nicotinic / genetics
Grant Support
ID/Acronym/Agency:
G0901697//Medical Research Council; G0901786//Medical Research Council; K08 HL097029/HL/NHLBI NIH HHS; K08 HL097029/HL/NHLBI NIH HHS; K12 HL089990/HL/NHLBI NIH HHS; K12HL089990/HL/NHLBI NIH HHS; P01 HL083069/HL/NHLBI NIH HHS; P01 HL083069/HL/NHLBI NIH HHS; P01 HL105339/HL/NHLBI NIH HHS; P01 HL105339/HL/NHLBI NIH HHS; R01 HL075478/HL/NHLBI NIH HHS; R01 HL075478/HL/NHLBI NIH HHS; R01 HL084323/HL/NHLBI NIH HHS; R01 HL084323/HL/NHLBI NIH HHS; R01 HL089856/HL/NHLBI NIH HHS; R01 HL089897/HL/NHLBI NIH HHS; R01 HL094635/HL/NHLBI NIH HHS; U01 HL089856/HL/NHLBI NIH HHS; U01 HL089856/HL/NHLBI NIH HHS; U01 HL089897/HL/NHLBI NIH HHS; U01 HL089897/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/FAM13A protein, human; 0/GTPase-Activating Proteins; 0/HHIP protein, human; 0/Membrane Glycoproteins; 0/Receptors, Nicotinic; 0/nicotinic receptor subunit alpha3; EC 4.2.1.3/Iron Regulatory Protein 2
Investigator
Investigator/Affiliation:
Harvey Coxson / ; Lisa Edwards / ; David Lomas / ; William MacNee / ; Edwin Silverman / ; Ruth Tal-Singer / ; Jørgen Vestbo / ; Julie Yates / ; Alvar Agusti / ; Per Bakke / ; Peter Calverley / ; Bartolome Celli / ; Courtney Crim / ; Bruce Miller / ; William MacNee / ; Stephen Rennard / ; Ruth Tal-Singer / ; Emiel Wouters / ; Yavor Ivanov / ; Kosta Kostov / ; Jean Bourbeau / ; Mark Fitzgerald / ; Paul Hernandez / ; Kieran Killian / ; Robert Levy / ; Francois Maltais / ; Denis O'Donnell / ; Jan Krepelka / ; Jørgen Vestbo / ; Emiel Wouters / ; Dean Quinn / ; Per Bakke / ; Mitja Kosnik / ; Alvar Agusti / ; Jaume Sauleda / ; Yuri Feschenko / ; Vladamir Gavrisyuk / ; Lyudmila Yashina / ; Nadezhda Monogarova / ; Peter Calverley / ; David Lomas / ; William MacNee / ; David Singh / ; Jadwiga Wedzicha / ; Antonio Anzueto / ; Sidney Braman / ; Richard Casaburi / ; Bart Celli / ; Glenn Giessel / ; Mark Gotfried / ; Gary Greenwald / ; Rancho Mirage / ; Nicola Hanania / ; Don Mahler / ; Barry Make / ; Stephen Rennard / ; Carolyn Rochester / ; Paul Scanlon / ; Dan Schuller / ; Frank Sciurba / ; Amir Sharafkhaneh / ; Thomas Siler / ; Edwin Silverman / ; Adam Wanner / ; Robert Wise / ; Richard ZuWallack / ; Jeffrey Curtis / ; Ella Kazerooni / ; Nicola Hanania / ; Philip Alapat / ; Venkata Bandi / ; Kalpalatha Guntupalli / ; Elizabeth Guy / ; Antara Mallampalli / ; Charles Trinh / ; Mustafa Atik / ; Dawn DeMeo / ; Craig Hersh / ; George Washko / ; Francine Jacobson / ; R Graham Barr / ; Byron Thomashow / ; John Austin / ; Neil MacIntyre / ; Lacey Washington / ; H Page McAdams / ; Richard Rosiello / ; Timothy Bresnahan / ; Charlene McEvoy / ; Joseph Tashjian / ; Robert Wise / ; Nadia Hansel / ; Robert Brown / ; Gregory Diette / ; Richard Casaburi / ; Janos Porszasz / ; Hans Fischer / ; Matt Budoff / ; Michael E DeBakey / ; Amir Sharafkhaneh / ; Charles Trinh / ; Hirani Kamal / ; Roham Darvishi / ; Dennis Niewoehner / ; Tadashi Allen / ; Quentin Anderson / ; Kathryn Rice / ; Marilyn Foreman / ; Gloria Westney / ; Eugene Berkowitz / ; Russell Bowler / ; Adam Friedlander / ; David Lynch / ; Joyce Schroeder / ; John Newell / ; Gerard Criner / ; Victor Kim / ; Nathaniel Marchetti / ; Aditi Satti / ; A James Mamary / ; Robert Steiner / ; Chandra Dass / ; William Bailey / ; Mark Dransfield / ; Hrudaya Nath / ; Joe Ramsdell / ; Paul Friedman / ; Geoffrey McLennan / ; Edwin J R van Beek / ; Brad Thompson / ; Dwight Look / ; Fernando Martinez / ; MeiLan Han / ; Ella Kazerooni / ; Christine Wendt / ; Tadashi Allen / ; Frank Sciurba / ; Joel Weissfeld / ; Carl Fuhrman / ; Jessica Bon / ; Antonio Anzueto / ; Sandra Adams / ; Carlos Orozco / ; Mario Ruiz / ; James Crapo / ; Edwin Silverman / ; Barry Make / ; Elizabeth Regan / ; Sarah Moyle / ; Douglas Stinson / ; Terri Beaty / ; Barbara Klanderman / ; Nan Laird / ; Christoph Lange / ; Michael Cho / ; Stephanie Santorico / ; John Hokanson / ; Dawn DeMeo / ; Nadia Hansel / ; Craig Hersh / ; Jacqueline Hetmanski / ; Tanda Murray / ; David Lynch / ; Joyce Schroeder / ; John Newell / ; John Reilly / ; Harvey Coxson / ; Philip Judy / ; Eric Hoffman / ; George Washko / ; Raul San Jose Estepar / ; James Ross / ; Rebecca Leek / ; Jordan Zach / ; Alex Kluiber / ; Jered Sieren / ; Heather Baumhauer / ; Verity McArthur / ; Dzimitry Kazlouski / ; Andrew Allen / ; Tanya Mann / ; Anastasia Rodionova / ; Robert Jensen / ; Homayoon Farzadegan / ; Stacey Meyerer / ; Shivam Chandan / ; Samantha Bragan / ; James Murphy / ; Douglas Everett / ; Carla Wilson / ; Ruthie Knowles / ; Amber Powell / ; Joe Piccoli / ; Maura Robinson / ; Margaret Forbes / ; Martina Wamboldt / ; John Hokanson / ; Marci Sontag / ; Jennifer Black-Shinn / ; Gregory Kinney / ; Joshua Benditt / ; Gerard Criner / ; Malcolm DeCamp / ; Philip Diaz / ; Mark Ginsburg / ; Larry Kaiser / ; Marcia Katz / ; Mark Krasna / ; Neil MacIntyre / ; Barry Make / ; Rob McKenna / ; Fernando Martinez / ; Zab Mosenifar / ; John Reilly / ; Andrew Ries / ; Paul Scanlon / ; Frank Sciurba / ; James Utz /
Comments/Corrections

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