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Clinical Trial
. 2013 Apr;132(4):431-41.
doi: 10.1007/s00439-012-1262-3. Epub 2013 Jan 9.

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

Mateusz Siedlinski  1 , 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; COPDGene and ECLIPSE Investigators
Collaborators, Affiliations
Clinical Trial

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

Mateusz Siedlinski et al. Hum Genet. 2013 Apr.

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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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Additive effects of variants in IREB2 and CHRNA3 on COPD development according to tertiles of pack years smoked among COPD cases *p < 0.05 **p < 5 × 10−8. Graph demonstrates the odds for COPD for specific tertiles of pack years smoked among COPD cases. All the unaffected control subjects (n = 1,872) were set as a reference group. Analyses were adjusted for 27 PCs and gender. PCs, Principal components for genetic ancestry; CHRNA3, cholinergic receptor, nicotinic, alpha 3; IREB2, iron-responsive element binding protein 2; COPD, chronic obstructive pulmonary disease
See this image and copyright information in PMC

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