@article{309c63ac11cd47498e0bc27eeb30c1f0,
title = "Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility",
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.",
author = "Mateusz Siedlinski and Dustin Tingley and Lipman, {Peter J.} and Cho, {Michael H.} and Litonjua, {Augusto A.} and David Sparrow and Per Bakke and Amund Gulsvik and Lomas, {David A.} and Wayne Anderson and Xiangyang Kong and Rennard, {Stephen I.} and Beaty, {Terri H.} and Hokanson, {John E.} and Crapo, {James D.} and Christoph Lange and Silverman, {Edwin K.}",
note = "Funding Information: 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 Astra-Zeneca, Boehringer Ingelheim, Novartis, Pfizer, and Sunovion.",
year = "2013",
month = apr,
doi = "10.1007/s00439-012-1262-3",
language = "English (US)",
volume = "132",
pages = "431--441",
journal = "Human genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "4",
}