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

Authors

  • Nadia N. Hansel
    • Department of Medicine, School of MedicineJohns Hopkins University
    • Department of Environmental Health Sciences, Bloomberg School of Public HealthJohns Hopkins University
  • Ingo Ruczinski
    • Department of Biostatistics, Bloomberg School of Public HealthJohns Hopkins University
  • Nicholas Rafaels
    • Department of Medicine, School of MedicineJohns Hopkins University
  • Don D. Sin
    • Division of Respirology, Department of Medicine, James Hogg Research Centre, St Paul’s HospitalUniversity of British Columbia
  • Denise Daley
    • Division of Respirology, Department of Medicine, James Hogg Research Centre, St Paul’s HospitalUniversity of British Columbia
  • Alla Malinina
    • Department of Medicine, School of MedicineJohns Hopkins University
  • Lili Huang
    • Department of Medicine, School of MedicineJohns Hopkins University
  • Andrew Sandford
    • Division of Respirology, Department of Medicine, James Hogg Research Centre, St Paul’s HospitalUniversity of British Columbia
  • Tanda Murray
    • Department of Medicine, School of MedicineJohns Hopkins University
  • Yoonhee Kim
    • Inherited Disease Research BranchNational Human Genome Research Institute, NIH
  • Candelaria Vergara
    • Department of Medicine, School of MedicineJohns Hopkins University
  • Susan R. Heckbert
    • Group Health Research InstituteGroup Health Cooperative
    • Department of Epidemiology, Cardiovascular Health Research UnitUniversity of Washington
  • Bruce M. Psaty
    • Departments of Medicine, Epidemiology and Health Services, Cardiovascular Health Research UnitUniversity of Washington
    • Group Health Research InstituteGroup Health Cooperative
  • Guo Li
    • Department of Medicine, Cardiovascular Health Research UnitUniversity of Washington
  • W. Mark Elliott
    • Department of Pathology and Laboratory Medicine, James Hogg Research Centre, St Paul’s HospitalUniversity of British Columbia
  • Farzian Aminuddin
    • Division of Respirology, Department of Medicine, James Hogg Research Centre, St Paul’s HospitalUniversity of British Columbia
  • Josée Dupuis
    • Department of BiostatisticsBoston University School of Public Health
    • The National Heart, Lung, and Blood Institute’s Framingham Heart Study
  • George T. O’Connor
    • Pulmonary Center, Department of MedicineBoston University School of Medicine
    • The National Heart, Lung, and Blood Institute’s Framingham Heart Study
  • Kimberly Doheny
    • Center for Inherited Disease Research (CIDR)Johns Hopkins University
  • Alan F. Scott
    • Center for Inherited Disease Research (CIDR)Johns Hopkins University
  • H. Marike Boezen
    • Department of EpidemiologyUniversity of Groningen, University Medical Center Groningen
    • Department of Genetics, GRIAC Research InstituteUniversity of Groningen, University Medical Center Groningen
  • Dirkje S. Postma
    • Department of PulmonologyUniversity of Groningen, University Medical Center Groningen
    • Department of Genetics, GRIAC Research InstituteUniversity of Groningen, University Medical Center Groningen
  • Joanna Smolonska
    • Department of GeneticsUniversity Medical Center Groningen, University of Groningen
    • Department of Genetics, GRIAC Research InstituteUniversity of Groningen, University Medical Center Groningen
  • Pieter Zanen
    • Division of Heart and LungsUniversity Medical Centre Utrecht
  • Firdaus A. Mohamed Hoesein
    • Division of Heart and LungsUniversity Medical Centre Utrecht
  • Harry J. de Koning
    • Department of Public HealthErasmus Medical Centre
  • Ronald G. Crystal
    • Department of Genetic MedicineWeill Cornell Medical College
  • Toshiko Tanaka
    • Clinical Research BranchNational Institute on Aging
  • Luigi Ferrucci
    • Clinical Research BranchNational Institute on Aging
  • Edwin Silverman
    • Channing LaboratoryBrigham and Women’s Hospital and Harvard Medical School
  • Emily Wan
    • Channing LaboratoryBrigham and Women’s Hospital and Harvard Medical School
  • Jorgen Vestbo
    • University of Copenhagen, Hvidovre Hospital
  • David A. Lomas
    • Department of Medicine, Cambridge Institute for Medical ResearchUniversity of Cambridge
  • John Connett
    • Division of Biostatistics, School of Public HealthUniversity of Minnesota
  • Robert A. Wise
    • Department of Medicine, School of MedicineJohns Hopkins University
  • Enid R. Neptune
    • Department of Medicine, School of MedicineJohns Hopkins University
  • Rasika A. Mathias
    • Department of Medicine, School of MedicineJohns Hopkins University
  • Peter D. Paré
    • Division of Respirology, Department of Medicine, James Hogg Research Centre, St Paul’s HospitalUniversity of British Columbia
  • Terri H. Beaty
    • Department of Epidemiology, Bloomberg School of Public HealthJohns Hopkins University
    • Department of Medicine, School of MedicineJohns Hopkins University
    • The Johns Hopkins Asthma and Allergy Center
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