Human Genetics

, Volume 132, Issue 1, pp 79–90 | Cite as

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

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.

Notes

Acknowledgments

This project was part of the Gene, Environment Association Studies (GENEVA) Consortium funded by the National Human Genome Research Institute (NHGRI) to enhance communication and collaboration among researchers conducting genome-wide studies of complex diseases. Our group benefited greatly from the work and efforts of the entire consortium, especially the Coordinating Center (directed by B. Weir and C. Laurie of the University of Washington) in data cleaning and preparation for submission to the Database for Genotypes and Phenotypes (dbGaP). Special thanks also to David Levine for additional, technical support. We also acknowledge the leadership of T. Manolio of NHGRI. We would also like to thank Helen Voelker and Kathy Farnell of the LHS Data Coordinating Center, University of Minnesota for assistance with the LHS database. We would also like to thank Corinne Boehm and Jane Romm of the Center for Inherited Disease Research, Johns Hopkins University, for technical support. The principal investigators and senior staff of the clinical and coordinating centers, the NHLBI, and members of the Safety and Data Monitoring Board of the Lung Health Study are as follows: Case Western Reserve University, Cleveland, OH: M.D. Altose, M.D. (Principal Investigator), C.D. Deitz, Ph.D. (Project Coordinator); Henry Ford Hospital, Detroit, MI: M.S. Eichenhorn, M.D. (Principal Investigator), K.J. Braden, A.A.S. (Project Coordinator), R.L. Jentons, M.A.L.L.P. (Project Coordinator); Johns Hopkins University School of Medicine, Baltimore, MD: R.A. Wise, M.D. (Principal Investigator), C.S. Rand, Ph.D. (Co-Principal Investigator), K.A. Schiller (Project Coordinator); Mayo Clinic, Rochester, MN: P.D. Scanlon, M.D. (Principal Investigator), G.M. Caron (Project Coordinator), K.S. Mieras, L.C. Walters; Oregon Health Sciences University, Portland: A.S. Buist, M.D. (Principal Investigator), L.R. Johnson, Ph.D. (LHS Pulmonary Function Coordinator), V.J. Bortz (Project Coordinator); University of Alabama at Birmingham: W.C. Bailey, M.D. (Principal Investigator), L.B. Gerald, Ph.D., M.S.P.H. (Project Coordinator); University of California, Los Angeles: D.P. Tashkin, M.D. (Principal Investigator), I.P. Zuniga (Project Coordinator); University of Manitoba, Winnipeg: N.R. Anthonisen, M.D. (Principal Investigator, Steering Committee Chair), J. Manfreda, M.D. (Co-Principal Investigator), R.P. Murray, Ph.D. (Co-Principal Investigator), S.C. Rempel-Rossum (Project Coordinator); University of Minnesota Coordinating Center, Minneapolis: J.E. Connett, Ph.D. (Principal Investigator), P.L. Enright, M.D., P.G. Lindgren, M.S., P. O’Hara, Ph.D., (LHS Intervention Coordinator), M.A. Skeans, M.S., H.T. Voelker; University of Pittsburgh, Pittsburgh, PA: R.M. Rogers, M.D. (Principal Investigator), M.E. Pusateri (Project Coordinator); University of Utah, Salt Lake City: R.E. Kanner, M.D. (Principal Investigator), G.M. Villegas (Project Coordinator); Safety and Data Monitoring Board: M. Becklake, M.D., B. Burrows, M.D. (deceased), P. Cleary, Ph.D., P. Kimbel, M.D. (Chairperson; deceased), L. Nett, R.N., R.R.T. (former member), J.K. Ockene, Ph.D., R.M. Senior, M.D. (Chairperson), G.L. Snider, M.D., W. Spitzer, M.D. (former member), O.D. Williams, Ph.D.; Morbidity and Mortality Review Board: T.E. Cuddy, M.D., R.S. Fontana, M.D., R.E. Hyatt, M.D., C.T. Lambrew, M.D., B.A. Mason, M.D., D.M. Mintzer, M.D., R.B. Wray, M.D.; National Heart, Lung, and Blood Institute staff, Bethesda, MD: S.S. Hurd, Ph.D. (Former Director, Division of Lung Diseases), J.P. Kiley, Ph.D. (Former Project Officer and Director, Division of Lung Diseases), G. Weinmann, M.D. (Former Project Officer and Director, Airway Biology and Disease Program, DLD), M.C. Wu, Ph.D. (Division of Epidemiology and Clinical Applications). Principal investigators and centers participating in ECLIPSE include: Bulgaria: Y. Ivanov, Pleven; K. Kostov, Sofia. Canada: J. Bourbeau, Montreal; M. Fitzgerald, Vancouver; P. Hernández, Halifax; K. Killian, Hamilton; R. Levy, Vancouver; F. Maltais, Montreal; .D O’Donnell, Kingston. Czech Republic: J. Krepelka, Praha. Denmark: J. Vestbo, Hvidovre. The Netherlands: E. Wouters, Horn. New Zealand: D. Quinn, Wellington. Norway: P. Bakke, Bergen, Slovenia: M. Kosnik, Golnik. Spain: A. Agusti, Jaume Sauleda, Palma de Mallorca. Ukraine: Y. Feschenko, Kiev; V. Gavrisyuk, Kiev; L. Yashina, Kiev. UK: L. Yashina, W. MacNee, Edinburgh; D. Singh, Manchester; J. Wedzicha, London. USA: A. Anzueto, San Antonio, TX; S. Braman, Providence. RI; R. Casaburi, Torrance CA; B. Celli, Boston, MA; G. Giessel, Richmond, VA; M. Gotfried, Phoenix, AZ; G. Greenwald, Rancho Mirage, CA; N. Hanania, Houston, TX; D, Mahler, Lebanon, NH; B. Make, Denver, CO; S. Rennard, Omaha, NE; C. Rochester, New Haven, CT; P. Scanlon, Rochester, MN; D. Schuller, Omaha, NE; F. Sciurba, Pittsburg, PA; A. Sharafkhaneh, Houston, TX; T. Siler, St Charles, MO; E. Silverman, Boston, MA; A. Wanner, Miami, FL; R. Wise, Baltimore, MD; R. ZuWallack, Hartford, CT. Steering Committee: H. Coxson (Canada), C. Crim (GlaxoSmithKline, USA), L. Edwards (GlaxoSmithKline, USA), D. Lomas (UK), W. MacNee (UK), E. Silverman (USA), R. Tal-Singer (Co-chair, GlaxoSmithKline, USA), J. Vestbo (Co-chair, Denmark), J. Yates (GlaxoSmithKline, USA). Scientific Committee: A. Agusti (Spain), P. Calverley (UK), B. Celli (USA), C. Crim (GlaxoSmithKline, USA), B. Miller (GlaxoSmithKline, US), W. MacNee (Chair, UK), S. Rennard (USA), R. Tal-Singer (GlaxoSmithKline, USA), E. Wouters (The Netherlands), J. Yates (GlaxoSmithKline, USA). Data deposition: Data can be obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000335.v1.p1 through dbGaP accession number phs000335.v1.pl. This research was supported by GENEVA (U01HG004738). The Lung Health Study I was supported by contract NIH/N01-HR-46002. Lung tissue validation studies were supported by the NHLBI HL095406-01. KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program. This CHS research was supported by NHLBI contracts HHSN268201200036C, N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center of Advancing Translational Technologies CTSI grant UL 1TR000124 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. FHS was funded by N01 HC 25195 from NHLBI. ECLIPSE was supported by GlaxoSmithKline. The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute. COPACETIC (acronym of COPD Pathology: Addressing Critical gaps, Early Treatment & diagnosis and Innovative Concepts) is funded by the European Union FP7 program, grant agreement number: 201379. GWAS genotyping was performed at the Center for Inhreited Disease Research under the support of NIH GEI grant U01 HG004438.

Ethical standards

All experiments described here comply with the current laws of the country in which they were performed.

Conflict of interest

The authors declare that they have no conflict of interest.

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)

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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

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