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Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility

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Abstract

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.

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References

  • Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, Mills G, Doheny K, Tsai YY, Chen WV, Shete S, Spitz MR, Houlston RS (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40(5):616–622

    Article  PubMed  CAS  Google Scholar 

  • Bell B, Rose CL, Damon H (1972) The Normative Aging Study: an interdisciplinary and longitudinal study of health and aging. Aging Hum Dev 3(3):5–17

    Article  Google Scholar 

  • Chappell SL, Daly L, Lotya J, Alsaegh A, Guetta-Baranes T, Roca J, Rabinovich R, Morgan K, Millar AB, Donnelly SC, Keatings V, MacNee W, Stolk J, Hiemstra PS, Miniati M, Monti S, O’Connor CM, Kalsheker N (2011) The role of IREB2 and transforming growth factor beta-1 genetic variants in COPD: a replication case–control study. BMC Med Genet 12:24

    Article  PubMed  CAS  Google Scholar 

  • Cho MH, Boutaoui N, Klanderman BJ, Sylvia JS, Ziniti JP, Hersh CP, DeMeo DL, Hunninghake GM, Litonjua AA, Sparrow D, Lange C, Won S, Murphy JR, Beaty TH, Regan EA, Make BJ, Hokanson JE, Crapo JD, Kong X, Anderson WH, Tal-Singer R, Lomas DA, Bakke P, Gulsvik A, Pillai SG, Silverman EK (2010) Variants in FAM13A are associated with chronic obstructive pulmonary disease. Nat Genet 42(3):200–202

    Article  PubMed  CAS  Google Scholar 

  • Cho MH, Castaldi PJ, Wan ES, Siedlinski M, Hersh CP, Demeo DL, Himes BE, Sylvia JS, Klanderman BJ, Ziniti JP, Lange C, Litonjua AA, Sparrow D, Regan EA, Make BJ, Hokanson JE, Murray T, Hetmanski JB, Pillai SG, Kong X, Anderson WH, Tal-Singer R, Lomas DA, Coxson HO, Edwards LD, MacNee W, Vestbo J, Yates JC, Agusti A, Calverley PM, Celli B, Crim C, Rennard S, Wouters E, Bakke P, Gulsvik A, Crapo JD, Beaty TH, Silverman EK (2012) A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. Hum Mol Genet 21(4):947–957

    Article  PubMed  CAS  Google Scholar 

  • DeMeo DL, Mariani T, Bhattacharya S, Srisuma S, Lange C, Litonjua A, Bueno R, Pillai SG, Lomas DA, Sparrow D, Shapiro SD, Criner GJ, Kim HP, Chen Z, Choi AM, Reilly J, Silverman EK (2009) Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene. Am J Hum Genet 85(4):493–502

    Article  PubMed  CAS  Google Scholar 

  • Dudbridge F, Gusnanto A (2008) Estimation of significance thresholds for genomewide association scans. Genet Epidemiol 32(3):227–234

    Article  PubMed  Google Scholar 

  • Ferris BG (1978) Epidemiology Standardization Project (American Thoracic Society). Am Rev Respir Dis 118(6 Pt 2):1–120

    PubMed  CAS  Google Scholar 

  • Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood DE (2003) A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 348(21):2059–2073

    Article  PubMed  Google Scholar 

  • Foreman MG, Kong X, DeMeo DL, Pillai SG, Hersh CP, Bakke P, Gulsvik A, Lomas DA, Litonjua AA, Shapiro SD, Tal-Singer R, Silverman EK (2011) Polymorphisms in surfactant protein-D are associated with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 44(3):316–322

    Article  PubMed  CAS  Google Scholar 

  • Fox J, Weisberg S (2011) An R companion to applied regression, 2nd edn. Sage, Thousand Oaks

    Google Scholar 

  • Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, Franceschini N, van Durme YM, Chen TH, Barr RG, Schabath MB, Couper DJ, Brusselle GG, Psaty BM, van Duijn CM, Rotter JI, Uitterlinden AG, Hofman A, Punjabi NM, Rivadeneira F, Morrison AC, Enright PL, North KE, Heckbert SR, Lumley T, Stricker BH, O’Connor GT, London SJ (2010) Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet 42(1):45–52

    Article  PubMed  CAS  Google Scholar 

  • Hersh CP, Pillai SG, Zhu G, Lomas DA, Bakke P, Gulsvik A, DeMeo DL, Klanderman BJ, Lazarus R, Litonjua AA, Sparrow D, Reilly JJ, Agusti A, Calverley PM, Donner CF, Levy RD, Make BJ, Pare PD, Rennard SI, Vestbo J, Wouters EF, Scholand MB, Coon H, Hoidal J, Silverman EK (2010) Multistudy fine mapping of chromosome 2q identifies XRCC5 as a chronic obstructive pulmonary disease susceptibility gene. Am J Respir Crit Care Med 182(5):605–613

    Article  PubMed  CAS  Google Scholar 

  • Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chen C, Goodman G, Field JK, Liloglou T, Xinarianos G, Cassidy A, McLaughlin J, Liu G, Narod S, Krokan HE, Skorpen F, Elvestad MB, Hveem K, Vatten L, Linseisen J, Clavel-Chapelon F, Vineis P, Bueno-de-Mesquita HB, Lund E, Martinez C, Bingham S, Rasmuson T, Hainaut P, Riboli E, Ahrens W, Benhamou S, Lagiou P, Trichopoulos D, Holcatova I, Merletti F, Kjaerheim K, Agudo A, Macfarlane G, Talamini R, Simonato L, Lowry R, Conway DI, Znaor A, Healy C, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P (2008) A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452(7187):633–637

    Article  PubMed  CAS  Google Scholar 

  • Imai K, Keele L, Tingley D (2010a) A general approach to causal mediation analysis. Psychol Methods 15(4):309–334

    Article  PubMed  Google Scholar 

  • Imai K, Keele L, Yamamoto T (2010b) Identification, inference and sensitivity analysis for causal mediation effects. Stat Sci 25:51–71

    Article  Google Scholar 

  • Kong X, Cho MH, Anderson W, Coxson HO, Muller N, Washko G, Hoffman EA, Bakke P, Gulsvik A, Lomas DA, Silverman EK, Pillai SG (2011) Genome-wide association study identifies BICD1 as a susceptibility gene for emphysema. Am J Respir Crit Care Med 183(1):43–49

    Article  PubMed  CAS  Google Scholar 

  • Lambrechts D, Buysschaert I, Zanen P, Coolen J, Lays N, Cuppens H, Groen HJ, Dewever W, van Klaveren RJ, Verschakelen J, Wijmenga C, Postma DS, Decramer M, Janssens W (2010) The 15q24/25 susceptibility variant for lung cancer and chronic obstructive pulmonary disease is associated with emphysema. Am J Respir Crit Care Med 181(5):486–493

    Article  PubMed  Google Scholar 

  • Liu JZ, Tozzi F, Waterworth DM, Pillai SG, Muglia P, Middleton L, Berrettini W, Knouff CW, Yuan X, Waeber G, Vollenweider P, Preisig M, Wareham NJ, Zhao JH, Loos RJ, Barroso I, Khaw KT, Grundy S, Barter P, Mahley R, Kesaniemi A, McPherson R, Vincent JB, Strauss J, Kennedy JL, Farmer A, McGuffin P, Day R, Matthews K, Bakke P, Gulsvik A, Lucae S, Ising M, Brueckl T, Horstmann S, Wichmann HE, Rawal R, Dahmen N, Lamina C, Polasek O, Zgaga L, Huffman J, Campbell S, Kooner J, Chambers JC, Burnett MS, Devaney JM, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Epstein S, Wilson JF, Wild SH, Campbell H, Vitart V, Reilly MP, Li M, Qu L, Wilensky R, Matthai W, Hakonarson HH, Rader DJ, Franke A, Wittig M, Schafer A, Uda M, Terracciano A, Xiao X, Busonero F, Scheet P, Schlessinger D, St Clair D, Rujescu D, Abecasis GR, Grabe HJ, Teumer A, Volzke H, Petersmann A, John U, Rudan I, Hayward C, Wright AF, Kolcic I, Wright BJ, Thompson JR, Balmforth AJ, Hall AS, Samani NJ, Anderson CA, Ahmad T, Mathew CG, Parkes M, Satsangi J, Caulfield M, Munroe PB, Farrall M, Dominiczak A, Worthington J, Thomson W, Eyre S, Barton A, Mooser V, Francks C, Marchini J (2010) Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 42(5):436–440

    Article  PubMed  CAS  Google Scholar 

  • Munafo MR, Timofeeva MN, Morris RW, Prieto-Merino D, Sattar N, Brennan P, Johnstone EC, Relton C, Johnson PC, Walther D, Whincup PH, Casas JP, Uhl GR, Vineis P, Padmanabhan S, Jefferis BJ, Amuzu A, Riboli E, Upton MN, Aveyard P, Ebrahim S, Hingorani AD, Watt G, Palmer TM, Timpson NJ, Davey Smith G (2012) Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. J Natl Cancer Inst 104(10):740–748

    Article  PubMed  CAS  Google Scholar 

  • Pearl J (2001) Direct and indirect effects. In: Breese JS, Koller D (eds) Proceedings of the 17th conference on uncertainty in artificial intelligence. Morgan Kaufman, San Francisco, pp 411–420

  • Pillai SG, Ge D, Zhu G, Kong X, Shianna KV, Need AC, Feng S, Hersh CP, Bakke P, Gulsvik A, Ruppert A, Lodrup Carlsen KC, Roses A, Anderson W, Rennard SI, Lomas DA, Silverman EK, Goldstein DB (2009) A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 5(3):e1000421

    Article  PubMed  Google Scholar 

  • Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38(8):904–909

    Article  PubMed  CAS  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575

    Article  PubMed  CAS  Google Scholar 

  • R Development Core Team (2010) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.Rproject.org

  • Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, Zielinski J (2007) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 176(6):532–555

    Article  PubMed  Google Scholar 

  • Regan EA, Hokanson JE, Murphy JR, Make B, Lynch DA, Beaty TH, Curran-Everett D, Silverman EK, Crapo JD (2010) Genetic epidemiology of COPD (COPDGene) study design. COPD 7(1):32–43

    Article  PubMed  Google Scholar 

  • Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M, Zhao JH, Ramasamy A, Zhai G, Vitart V, Huffman JE, Igl W, Albrecht E, Deloukas P, Henderson J, Granell R, McArdle WL, Rudnicka AR, Barroso I, Loos RJ, Wareham NJ, Mustelin L, Rantanen T, Surakka I, Imboden M, Wichmann HE, Grkovic I, Jankovic S, Zgaga L, Hartikainen AL, Peltonen L, Gyllensten U, Johansson A, Zaboli G, Campbell H, Wild SH, Wilson JF, Glaser S, Homuth G, Volzke H, Mangino M, Soranzo N, Spector TD, Polasek O, Rudan I, Wright AF, Heliovaara M, Ripatti S, Pouta A, Naluai AT, Olin AC, Toren K, Cooper MN, James AL, Palmer LJ, Hingorani AD, Wannamethee SG, Whincup PH, Smith GD, Ebrahim S, McKeever TM, Pavord ID, MacLeod AK, Morris AD, Porteous DJ, Cooper C, Dennison E, Shaheen S, Karrasch S, Schnabel E, Schulz H, Grallert H, Bouatia-Naji N, Delplanque J, Froguel P, Blakey JD, Britton JR, Morris RW, Holloway JW, Lawlor DA, Hui J, Nyberg F, Jarvelin MR, Jackson C, Kahonen M, Kaprio J, Probst-Hensch NM, Koch B, Hayward C, Evans DM, Elliott P, Strachan DP, Hall IP, Tobin MD (2010) Genome-wide association study identifies five loci associated with lung function. Nat Genet 42(1):36–44

    Article  PubMed  CAS  Google Scholar 

  • Robins JM, Greenland S (1992) Identifiability and exchangeability for direct and indirect effects. Epidemiology 3(2):143–155

    Article  PubMed  CAS  Google Scholar 

  • Saccone NL, Culverhouse RC, Schwantes-An TH, Cannon DS, Chen X, Cichon S, Giegling I, Han S, Han Y, Keskitalo-Vuokko K, Kong X, Landi MT, Ma JZ, Short SE, Stephens SH, Stevens VL, Sun L, Wang Y, Wenzlaff AS, Aggen SH, Breslau N, Broderick P, Chatterjee N, Chen J, Heath AC, Heliovaara M, Hoft NR, Hunter DJ, Jensen MK, Martin NG, Montgomery GW, Niu T, Payne TJ, Peltonen L, Pergadia ML, Rice JP, Sherva R, Spitz MR, Sun J, Wang JC, Weiss RB, Wheeler W, Witt SH, Yang BZ, Caporaso NE, Ehringer MA, Eisen T, Gapstur SM, Gelernter J, Houlston R, Kaprio J, Kendler KS, Kraft P, Leppert MF, Li MD, Madden PA, Nothen MM, Pillai S, Rietschel M, Rujescu D, Schwartz A, Amos CI, Bierut LJ (2010) Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PLoS Genet 6(8):e1001053

    Google Scholar 

  • Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP, Manolescu A, Thorleifsson G, Stefansson H, Ingason A, Stacey SN, Bergthorsson JT, Thorlacius S, Gudmundsson J, Jonsson T, Jakobsdottir M, Saemundsdottir J, Olafsdottir O, Gudmundsson LJ, Bjornsdottir G, Kristjansson K, Skuladottir H, Isaksson HJ, Gudbjartsson T, Jones GT, Mueller T, Gottsater A, Flex A, Aben KK, de Vegt F, Mulders PF, Isla D, Vidal MJ, Asin L, Saez B, Murillo L, Blondal T, Kolbeinsson H, Stefansson JG, Hansdottir I, Runarsdottir V, Pola R, Lindblad B, van Rij AM, Dieplinger B, Haltmayer M, Mayordomo JI, Kiemeney LA, Matthiasson SE, Oskarsson H, Tyrfingsson T, Gudbjartsson DF, Gulcher JR, Jonsson S, Thorsteinsdottir U, Kong A, Stefansson K (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452(7187):638–642

    Article  PubMed  CAS  Google Scholar 

  • Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F, Sulem P, Rafnar T, Esko T, Walter S, Gieger C, Rawal R, Mangino M, Prokopenko I, Magi R, Keskitalo K, Gudjonsdottir IH, Gretarsdottir S, Stefansson H, Thompson JR, Aulchenko YS, Nelis M, Aben KK, den Heijer M, Dirksen A, Ashraf H, Soranzo N, Valdes AM, Steves C, Uitterlinden AG, Hofman A, Tonjes A, Kovacs P, Hottenga JJ, Willemsen G, Vogelzangs N, Doring A, Dahmen N, Nitz B, Pergadia ML, Saez B, De Diego V, Lezcano V, Garcia-Prats MD, Ripatti S, Perola M, Kettunen J, Hartikainen AL, Pouta A, Laitinen J, Isohanni M, Huei-Yi S, Allen M, Krestyaninova M, Hall AS, Jones GT, van Rij AM, Mueller T, Dieplinger B, Haltmayer M, Jonsson S, Matthiasson SE, Oskarsson H, Tyrfingsson T, Kiemeney LA, Mayordomo JI, Lindholt JS, Pedersen JH, Franklin WA, Wolf H, Montgomery GW, Heath AC, Martin NG, Madden PA, Giegling I, Rujescu D, Jarvelin MR, Salomaa V, Stumvoll M, Spector TD, Wichmann HE, Metspalu A, Samani NJ, Penninx BW, Oostra BA, Boomsma DI, Tiemeier H, van Duijn CM, Kaprio J, Gulcher JR, McCarthy MI, Peltonen L, Thorsteinsdottir U, Stefansson K (2010) Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 42(5):448–453

    Article  PubMed  CAS  Google Scholar 

  • Valeri L, VanderWeele TJ (2012) Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods (in press)

  • Van Durme YM, Eijgelsheim M, Joos GF, Hofman A, Uitterlinden AG, Brusselle GG, Stricker BH (2010) Hedgehog-interacting protein is a COPD susceptibility gene: the Rotterdam Study. Eur Respir J 36(1):89–95

    Article  PubMed  Google Scholar 

  • VanderWeele TJ, Vansteelandt S (2010) Odds ratios for mediation analysis for a dichotomous outcome. Am J Epidemiol 172(12):1339–1348

    Article  PubMed  Google Scholar 

  • VanderWeele TJ, Asomaning K, Tchetgen Tchetgen EJ, Han Y, Spitz, Shete S, Wu X, Gaborieau V, Wang Y, McLaughlin J, Hung RJ, Brennan P, Amos CI, Christiani DC, Lin X (2012) Genetic variants on 15q25.1, smoking, and lung cancer: an assessment of mediation and interaction. Am J Epidemiol 175(10):1013–1020

    Article  PubMed  Google Scholar 

  • Vansteelandt S (2009) Estimating direct effects in cohort and case-control studies. Epidemiology 20(6):851–860

    Article  PubMed  Google Scholar 

  • Vansteelandt S, Goetgeluk S, Lutz S, Waldman I, Lyon H, Schadt EE, Weiss ST, Lange C (2009) On the adjustment for covariates in genetic association analysis: a novel, simple principle to infer direct causal effects. Genet Epidemiol 33(5):394–405

    Article  PubMed  Google Scholar 

  • Vestbo J, Anderson W, Coxson HO, Crim C, Dawber F, Edwards L, Hagan G, Knobil K, Lomas DA, MacNee W, Silverman EK, Tal-Singer R (2008) Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). Eur Respir J 31(4):869–873

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Spitz MR, Amos CI, Wilkinson AV, Wu X, Shete S (2010) Mediating effects of smoking and chronic obstructive pulmonary disease on the relation between the CHRNA5-A3 genetic locus and lung cancer risk. Cancer 116(14):3458–3462

    Article  PubMed  CAS  Google Scholar 

  • Wilk JB, Chen TH, Gottlieb DJ, Walter RE, Nagle MW, Brandler BJ, Myers RH, Borecki IB, Silverman EK, Weiss ST, O’Connor GT (2009) A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet 5(3):e1000429

    Article  PubMed  Google Scholar 

  • Wilk JB, Shrine NR, Loehr LR, Zhao JH, Manichaikul A, Lopez LM, Smith AV, Heckbert SR, Smolonska J, Tang W, Loth DW, Curjuric I, Hui J, Cho MH, Latourelle JC, Henry AP, Aldrich M, Bakke P, Beaty TH, Bentley AR, Borecki IB, Brusselle GG, Burkart KM, Chen TH, Couper D, Crapo JD, Davies G, Dupuis J, Franceschini N, Gulsvik A, Hancock DB, Harris TB, Hofman A, Imboden M, James AL, Khaw KT, Lahousse L, Launer LJ, Litonjua A, Liu Y, Lohman KK, Lomas DA, Lumley T, Marciante KD, McArdle WL, Meibohm B, Morrison AC, Musk AW, Myers RH, North KE, Postma DS, Psaty BM, Rich SS, Rivadeneira F, Rochat T, Rotter JI, Soler Artigas M, Starr JM, Uitterlinden AG, Wareham NJ, Wijmenga C, Zanen P, Province MA, Silverman EK, Deary IJ, Palmer LJ, Cassano PA, Gudnason V, Barr RG, Loos RJ, Strachan DP, London SJ, Boezen HM, Probst-Hensch N, Gharib SA, Hall IP, O’Connor GT, Tobin MD, Stricker BH (2012) Genome wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. Am J Respir Crit Care Med 186(7):622–632

    Google Scholar 

  • Young RP, Hopkins RJ, Whittington CF, Hay BA, Epton MJ, Gamble GD (2011) Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD. PLoS One 6(2):e16476

    Article  PubMed  CAS  Google Scholar 

  • Zhu G, Warren L, Aponte J, Gulsvik A, Bakke P, Anderson WH, Lomas DA, Silverman EK, Pillai SG (2007) The SERPINE2 gene is associated with chronic obstructive pulmonary disease in two large populations. Am J Respir Crit Care Med 176(2):167–173

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful to Prof. Kosuke Imai from the Department of Politics at the Princeton University and Dr Stijn Vansteelandt from the Department of Applied Mathematics and Computer Sciences at the Ghent University for their comprehensive help with mediation analysis. This work was supported by US National Institutes of Health (NIH) grants R01 HL075478, R01 HL084323, P01 HL083069, P01 HL105339, and U01 HL089856 (E.K.S.); K12HL089990 and K08 HL097029 (M.H.C); and U01 HL089897 (J.D.C.). M.S. is a recipient of a postdoctoral fellowship from the Niels Stensen Foundation. The NETT was supported by the National Heart, Lung, and Blood Institute, the Centers for Medicare and Medicaid Services and the Agency for Healthcare Research and Quality. The NAS is supported by the Cooperative Studies Program/ERIC of the US Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). The Norway GenKOLS study (Genetics of Chronic Obstructive Lung Disease, GSK code RES11080) and the ECLIPSE study (clinicaltrials.gov identifier NCT00292552; GSK code SCO104960) are funded by GlaxoSmithKline. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, and Sunovion.

Conflict of interest

No competing interests: MS, DT, AG, AAL, PJL, CL, DS; GlaxoSmithKline employee: WA, XK; NHLBI grant: JEH, THB; NIH grant: MHC, EKS, JDC; GlaxoSmithKline grant: EKS, DAL, PB; COPD Foundation grant: EKS, JDC; GlaxoSmithKline consulting fee or honorarium and support for travel to meetings for the study or other purposes: EKS, DAL; COPD Foundation support for travel to meetings for the study or other purposes: EKS, JDC; AstraZeneca and GlaxoSmithKline—payment for lectures including service on speakers bureaus and consultancy (outside the submitted work): EKS, PB; Pfizer—payment for lectures including service on speakers bureaus and consultancy (outside the submitted work): PB; GlaxoSmithKline—board membership, consultancy, payment for lectures including service on speakers bureaus and consultancy (outside the submitted work): DAL; Boehringer Ingelheim consultancy (outside the submitted work): DAL; GlaxoSmithKline fees for participation in review activities such as data monitoring boards, statistical analysis, end point committees, and the like: DAL; Consulting fee or honorarium from AstraZeneca, Novartis, Otsuka: SIR; Grant from AstraZeneca, Biomarck, Centocor, Mpex, Nabi, Novartis, Otsuka: SIR; Almirall, Novartis, Nycomed, Pfizer board membership (outside the submitted work): SIR; Almirall, AstraZeneca, Boehringer Ingelheim, California Allergy Society, Creative Educational Concept, France Foundation, GlaxoSmithKline, Information TV, Network for Continuing Education, Novartis, Nycomed, Pfizer—travel/accommodations expenses covered or reimbursed (outside the submitted work): SIR; Able Associates, Adelphi Research, APT Pharma/Britnall, Aradigm, AstraZeneca, Boehringer Ingelheim, Chiesi, CommonHealth, Consult Complete, COPDForum, Data Monitor, Decision Resource, Defined Health, Dey, Dunn Group, Easton Associates, Equinox, Gerson, GlaxoSmithKline, Infomed, KOL Connection, M. Pankove, MedaCorp, MDRx Financial, Mpex, Oriel Therapeutics, Otsuka, Pennside, PharmaVentures, Pharmaxis, Price Waterhouse, Propagate, Pulmatrix, Reckner Associates, Recruiting Resources, Roche, Schlesinger Medical, Scimed, Sudler and Hennessey, TargeGen, Theravance, UBC, Uptake Medical, VantagePoint Mangement—consultancy (outside the submitted work): SIR.

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Authors and Affiliations

  1. Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA

    Mateusz Siedlinski, Michael H. Cho, Augusto A. Litonjua & Edwin K. Silverman

  2. Department of Government, Harvard University, Cambridge, MA, USA

    Dustin Tingley

  3. Department of Biostatistics, Harvard School of Public Health, Boston, USA

    Peter J. Lipman & Christoph Lange

  4. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Michael H. Cho, Augusto A. Litonjua & Edwin K. Silverman

  5. Veterans Affairs Boston Healthcare System and Boston University Schools of Public Health and Medicine, Boston, MA, USA

    David Sparrow

  6. Department of Thoracic Medicine, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway

    Per Bakke & Amund Gulsvik

  7. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

    David A. Lomas

  8. GlaxoSmithKline Research and Development, Research Triangle Park, NC, USA

    Wayne Anderson

  9. GlaxoSmithKline Research and Development, King of Prussia, PA, USA

    Xiangyang Kong

  10. Department of Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    Stephen I. Rennard

  11. Johns Hopkins School of Public Health, Baltimore, MD, USA

    Terri H. Beaty

  12. Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA

    John E. Hokanson

  13. Department of Medicine, National Jewish Health, Denver, CO, USA

    James D. Crapo

Authors
  1. Mateusz Siedlinski
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  2. Dustin Tingley
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  3. Peter J. Lipman
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  4. Michael H. Cho
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  5. Augusto A. Litonjua
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  6. David Sparrow
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  7. Per Bakke
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  8. Amund Gulsvik
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  9. David A. Lomas
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  10. Wayne Anderson
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  11. Xiangyang Kong
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  12. Stephen I. Rennard
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  13. Terri H. Beaty
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  14. John E. Hokanson
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  15. James D. Crapo
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  16. Christoph Lange
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  17. Edwin K. Silverman
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Consortia

and the COPDGene and ECLIPSE Investigators

Corresponding author

Correspondence to Edwin K. Silverman.

Additional information

The members of NETT, COPDGene and ECLIPSE Investigators are listed in the Appendix.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1665 kb)

Appendix

Appendix

ECLIPSE Steering Committee

Harvey Coxson (Canada), Lisa Edwards (GlaxoSmithKline, USA), David Lomas (UK), William MacNee (UK), Edwin Silverman (USA), Ruth Tal-Singer (Co-chair, GlaxoSmithKline, USA), Jørgen Vestbo (Co-chair, Denmark), Julie Yates (GlaxoSmithKline, USA).

ECLIPSE Scientific Committee

Alvar Agusti (Spain), Per Bakke (Norway), Peter Calverley (UK), Bartolome Celli (USA), Courtney Crim (GlaxoSmithKline, USA), Bruce Miller (GlaxoSmithKline, UK), William MacNee (Chair, UK), Stephen Rennard (USA), Ruth Tal-Singer (GlaxoSmithKline, USA), Emiel Wouters (The Netherlands).

ECLIPSE Investigators

Bulgaria: Yavor Ivanov, Pleven; Kosta Kostov, Sofia. Canada: Jean Bourbeau, Montreal, Que; Mark Fitzgerald, Vancouver, BC; Paul Hernandez, Halifax, NS; Kieran Killian, Hamilton, On; Robert Levy, Vancouver, BC; Francois Maltais, Montreal, Que; Denis O’Donnell, Kingston, On. Czech Republic: Jan Krepelka, Praha. Denmark: Jørgen Vestbo, Hvidovre. Netherlands: Emiel Wouters, Horn-Maastricht. New Zealand: Dean Quinn, Wellington. Norway: Per Bakke, Bergen. Slovenia: Mitja Kosnik, Golnik. Spain: Alvar Agusti, Jaume Sauleda, Palma de Mallorca. Ukraine: Yuri Feschenko, Kiev; Vladamir Gavrisyuk, Kiev; Lyudmila Yashina, Kiev; Nadezhda Monogarova, Donetsk. United Kingdom: Peter Calverley, Liverpool; David Lomas, Cambridge; William MacNee, Edinburgh; David Singh, Manchester; Jadwiga Wedzicha, London. United States of America: Antonio Anzueto, San Antonio, TX; Sidney Braman, Providence, RI; Richard Casaburi, Torrance CA; Bart Celli, Boston, MA; Glenn Giessel, Richmond, VA; Mark Gotfried, Phoenix, AZ; Gary Greenwald, Rancho Mirage, CA; Nicola Hanania, Houston, TX; Don Mahler, Lebanon, NH; Barry Make, Denver, CO; Stephen Rennard, Omaha, NE; Carolyn Rochester, New Haven, CT; Paul Scanlon, Rochester, MN; Dan Schuller, Omaha, NE; Frank Sciurba, Pittsburgh, PA; Amir Sharafkhaneh, Houston, TX; Thomas Siler, St. Charles, MO, Edwin Silverman, Boston, MA; Adam Wanner, Miami, FL; Robert Wise, Baltimore, MD; Richard ZuWallack, Hartford, CT.

COPDGene Investigators

The members of the COPDGene study group as of June 2010

Ann Arbor VA: Jeffrey Curtis, MD (PI), Ella Kazerooni, MD (RAD)

Baylor College of Medicine, Houston, TX: Nicola Hanania, MD, MS (PI), Philip Alapat, MD, Venkata Bandi, MD, Kalpalatha Guntupalli, MD, Elizabeth Guy, MD, Antara Mallampalli, MD, Charles Trinh, MD (RAD), Mustafa Atik, MD

Brigham and Women’s Hospital, Boston, MA: Dawn DeMeo, MD, MPH (Co-PI), Craig Hersh, MD, MPH (Co-PI), George Washko, MD, Francine Jacobson, MD, MPH (RAD)

Columbia University, New York, NY: R. Graham Barr, MD, DrPH (PI), Byron Thomashow, MD, John Austin, MD (RAD)

Duke University Medical Center, Durham, NC: Neil MacIntyre, Jr., MD (PI), Lacey Washington, MD (RAD), H Page McAdams, MD (RAD)

Fallon Clinic, Worcester, MA: Richard Rosiello, MD (PI), Timothy Bresnahan, MD (RAD)

Health Partners Research Foundation, Minneapolis, MN: Charlene McEvoy, MD, MPH (PI), Joseph Tashjian, MD (RAD)

Johns Hopkins University, Baltimore, MD: Robert Wise, MD (PI), Nadia Hansel, MD, MPH, Robert Brown, MD (RAD), Gregory Diette, MD

Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Los Angeles, CA: Richard Casaburi, MD (PI), Janos Porszasz, MD, PhD, Hans Fischer, MD, PhD (RAD), Matt Budoff, MD

Michael E. DeBakey VAMC, Houston, TX: Amir Sharafkhaneh, MD (PI), Charles Trinh, MD (RAD), Hirani Kamal, MD, Roham Darvishi, MD

Minneapolis VA: Dennis Niewoehner, MD (PI), Tadashi Allen, MD (RAD), Quentin Anderson, MD (RAD), Kathryn Rice, MD

Morehouse School of Medicine, Atlanta, GA: Marilyn Foreman, MD, MS (PI), Gloria Westney, MD, MS, Eugene Berkowitz, MD, PhD (RAD)

National Jewish Health, Denver, CO: Russell Bowler, MD, PhD (PI), Adam Friedlander, MD, David Lynch, MB (RAD), Joyce Schroeder, MD (RAD), John Newell, Jr., MD (RAD)

Temple University, Philadelphia, PA: Gerard Criner, MD (PI), Victor Kim, MD, Nathaniel Marchetti, DO, Aditi Satti, MD, A. James Mamary, MD, Robert Steiner, MD (RAD), Chandra Dass, MD (RAD)

University of Alabama, Birmingham, AL: William Bailey, MD (PI), Mark Dransfield, MD (Co-PI), Hrudaya Nath, MD (RAD)

University of California, San Diego, CA: Joe Ramsdell, MD (PI), Paul Friedman, MD (RAD)

University of Iowa, Iowa City, IA: Geoffrey McLennan, MD, PhD (PI), Edwin JR van Beek, MD, PhD (RAD), Brad Thompson, MD (RAD), Dwight Look, MD

University of Michigan, Ann Arbor, MI: Fernando Martinez, MD (PI), MeiLan Han, MD, Ella Kazerooni, MD (RAD)

University of Minnesota, Minneapolis, MN: Christine Wendt, MD (PI), Tadashi Allen, MD (RAD)

University of Pittsburgh, Pittsburgh, PA: Frank Sciurba, MD (PI), Joel Weissfeld, MD, MPH, Carl Fuhrman, MD (RAD), Jessica Bon, MD

University of Texas Health Science Center at San Antonio, San Antonio, TX: Antonio Anzueto, MD (PI), Sandra Adams, MD, Carlos Orozco, MD, Mario Ruiz, MD (RAD)

Administrative Core: James Crapo, MD (PI), Edwin Silverman, MD, PhD (PI), Barry Make, MD, Elizabeth Regan, MD, Sarah Moyle, MS, Douglas Stinson

Genetic Analysis Core: Terri Beaty, PhD, Barbara Klanderman, PhD, Nan Laird, PhD, Christoph Lange, PhD, Michael Cho, MD, Stephanie Santorico, PhD, John Hokanson, MPH, PhD, Dawn DeMeo, MD, MPH, Nadia Hansel, MD, MPH, Craig Hersh, MD, MPH, Jacqueline Hetmanski, MS, Tanda Murray.

Imaging Core: David Lynch, MB, Joyce Schroeder, MD, John Newell, Jr., MD, John Reilly, MD, Harvey Coxson, PhD, Philip Judy, PhD, Eric Hoffman, PhD, George Washko, MD, Raul San Jose Estepar, PhD, James Ross, MSc, Rebecca Leek, Jordan Zach, Alex Kluiber, Jered Sieren, Heather Baumhauer, Verity McArthur, Dzimitry Kazlouski, Andrew Allen, Tanya Mann, Anastasia Rodionova

PFT QA Core, LDS Hospital, Salt Lake City, UT: Robert Jensen, PhD

Biological Repository, Johns Hopkins University, Baltimore, MD: Homayoon Farzadegan, PhD, Stacey Meyerer, Shivam Chandan, Samantha Bragan

Data Coordinating Center and Biostatistics, National Jewish Health, Denver, CO: James Murphy, PhD, Douglas Everett, PhD, Carla Wilson, MS, Ruthie Knowles, Amber Powell, Joe Piccoli, Maura Robinson, Margaret Forbes, Martina Wamboldt

Epidemiology Core, University of Colorado School of Public Health, Denver, CO: John Hokanson, MPH, PhD, Marci Sontag, PhD, Jennifer Black-Shinn, MPH, Gregory Kinney, MPH.

We acknowledge the co-investigators in the NETT Genetics Ancillary Study including 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, and James Utz.

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Siedlinski, M., Tingley, D., Lipman, P.J. et al. Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility. Hum Genet 132, 431–441 (2013). https://doi.org/10.1007/s00439-012-1262-3

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