Human Genetics

, Volume 132, Issue 1, pp 79–90

Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD

  • Nadia N. Hansel
  • Ingo Ruczinski
  • Nicholas Rafaels
  • Don D. Sin
  • Denise Daley
  • Alla Malinina
  • Lili Huang
  • Andrew Sandford
  • Tanda Murray
  • Yoonhee Kim
  • Candelaria Vergara
  • Susan R. Heckbert
  • Bruce M. Psaty
  • Guo Li
  • W. Mark Elliott
  • Farzian Aminuddin
  • Josée Dupuis
  • George T. O’Connor
  • Kimberly Doheny
  • Alan F. Scott
  • H. Marike Boezen
  • Dirkje S. Postma
  • Joanna Smolonska
  • Pieter Zanen
  • Firdaus A. Mohamed Hoesein
  • Harry J. de Koning
  • Ronald G. Crystal
  • Toshiko Tanaka
  • Luigi Ferrucci
  • Edwin Silverman
  • Emily Wan
  • Jorgen Vestbo
  • David A. Lomas
  • John Connett
  • Robert A. Wise
  • Enid R. Neptune
  • Rasika A. Mathias
  • Peter D. Paré
  • Terri H. Beaty
  • Kathleen C. Barnes
Original Investigation

DOI: 10.1007/s00439-012-1219-6

Cite this article as:
Hansel, N.N., Ruczinski, I., Rafaels, N. et al. Hum Genet (2013) 132: 79. doi:10.1007/s00439-012-1219-6

Abstract

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

Supplementary material

439_2012_1219_MOESM1_ESM.docx (90 kb)
Supplementary material 1 (DOCX 89 kb)
439_2012_1219_MOESM2_ESM.pdf (613 kb)
Supplementary material 2 (PDF 612 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Nadia N. Hansel
    • 1
    • 2
  • Ingo Ruczinski
    • 3
  • Nicholas Rafaels
    • 1
  • Don D. Sin
    • 4
  • Denise Daley
    • 4
  • Alla Malinina
    • 1
  • Lili Huang
    • 1
  • Andrew Sandford
    • 4
  • Tanda Murray
    • 1
  • Yoonhee Kim
    • 5
  • Candelaria Vergara
    • 1
  • Susan R. Heckbert
    • 27
    • 28
  • Bruce M. Psaty
    • 7
    • 27
  • Guo Li
    • 6
  • W. Mark Elliott
    • 8
  • Farzian Aminuddin
    • 4
  • Josée Dupuis
    • 9
    • 11
  • George T. O’Connor
    • 10
    • 11
  • Kimberly Doheny
    • 12
  • Alan F. Scott
    • 12
  • H. Marike Boezen
    • 13
    • 16
  • Dirkje S. Postma
    • 14
    • 16
  • Joanna Smolonska
    • 15
    • 16
  • Pieter Zanen
    • 17
  • Firdaus A. Mohamed Hoesein
    • 17
  • Harry J. de Koning
    • 18
  • Ronald G. Crystal
    • 19
  • Toshiko Tanaka
    • 20
  • Luigi Ferrucci
    • 20
  • Edwin Silverman
    • 21
  • Emily Wan
    • 21
  • Jorgen Vestbo
    • 22
  • David A. Lomas
    • 23
  • John Connett
    • 24
  • Robert A. Wise
    • 1
  • Enid R. Neptune
    • 1
  • Rasika A. Mathias
    • 1
  • Peter D. Paré
    • 4
  • Terri H. Beaty
    • 25
  • Kathleen C. Barnes
    • 1
    • 26
  1. 1.Department of Medicine, School of MedicineJohns Hopkins UniversityBaltimoreUSA
  2. 2.Department of Environmental Health Sciences, Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreUSA
  3. 3.Department of Biostatistics, Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreUSA
  4. 4.Division of Respirology, Department of Medicine, James Hogg Research Centre, St Paul’s HospitalUniversity of British ColumbiaVancouverCanada
  5. 5.Inherited Disease Research BranchNational Human Genome Research Institute, NIHBaltimoreUSA
  6. 6.Department of Medicine, Cardiovascular Health Research UnitUniversity of WashingtonSeattleUSA
  7. 7.Departments of Medicine, Epidemiology and Health Services, Cardiovascular Health Research UnitUniversity of WashingtonSeattleUSA
  8. 8.Department of Pathology and Laboratory Medicine, James Hogg Research Centre, St Paul’s HospitalUniversity of British ColumbiaVancouverCanada
  9. 9.Department of BiostatisticsBoston University School of Public HealthBostonUSA
  10. 10.Pulmonary Center, Department of MedicineBoston University School of MedicineBostonUSA
  11. 11.The National Heart, Lung, and Blood Institute’s Framingham Heart StudyFraminghamUSA
  12. 12.Center for Inherited Disease Research (CIDR)Johns Hopkins UniversityBaltimoreUSA
  13. 13.Department of EpidemiologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
  14. 14.Department of PulmonologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
  15. 15.Department of GeneticsUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
  16. 16.Department of Genetics, GRIAC Research InstituteUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
  17. 17.Division of Heart and LungsUniversity Medical Centre UtrechtUtrechtThe Netherlands
  18. 18.Department of Public HealthErasmus Medical CentreRotterdamThe Netherlands
  19. 19.Department of Genetic MedicineWeill Cornell Medical CollegeNew YorkUSA
  20. 20.Clinical Research BranchNational Institute on AgingBaltimoreUSA
  21. 21.Channing LaboratoryBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  22. 22.University of Copenhagen, Hvidovre HospitalHvidovreDenmark
  23. 23.Department of Medicine, Cambridge Institute for Medical ResearchUniversity of CambridgeCambridgeUK
  24. 24.Division of Biostatistics, School of Public HealthUniversity of MinnesotaSt. PaulUSA
  25. 25.Department of Epidemiology, Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreUSA
  26. 26.The Johns Hopkins Asthma and Allergy CenterBaltimoreUSA
  27. 27.Group Health Research InstituteGroup Health CooperativeSeattleUSA
  28. 28.Department of Epidemiology, Cardiovascular Health Research UnitUniversity of WashingtonSeattleUSA