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Chronic obstructive pulmonary disease
Original article
Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease
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  1. John M Brehm1,
  2. Koichi Hagiwara2,
  3. Yohannes Tesfaigzi3,
  4. Shannon Bruse3,
  5. Thomas J Mariani4,
  6. Soumyaroop Bhattacharya4,
  7. Nadia Boutaoui1,
  8. John P Ziniti5,
  9. Manuel E Soto-Quiros6,
  10. Lydiana Avila6,
  11. Michael H Cho5,7,8,
  12. Blanca Himes5,
  13. Augusto A Litonjua5,7,8,9,
  14. Francine Jacobson10,
  15. Per Bakke11,
  16. Amund Gulsvik11,
  17. Wayne H Anderson12,
  18. David A Lomas13,
  19. Erick Forno14,
  20. Soma Datta5,
  21. Edwin K Silverman5,7,8,15,
  22. Juan C Celedón1
  1. 1Division of Pediatric Pulmonary Medicine, Allergy, and Immunology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA
  2. 2Saitama Medical University Hospital and Institute, Saitama, Japan
  3. 3Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA
  4. 4University of Rochester Medical Center, Rochester, New York, USA
  5. 5Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts, USA
  6. 6Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica
  7. 7Division of Pulmonary/Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  8. 8Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  9. 9Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
  10. 10Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts, USA
  11. 11Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway
  12. 12GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, USA
  13. 13Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
  14. 14Division of Pediatric Pulmonology, Department of Pediatrics, University of Miami, Miami, Florida, USA
  15. 15Center for Genomic Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  1. Correspondence to Dr Juan C Celedón, Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; juan.celedon{at}chp.edu

Abstract

Rationale Traditional genome-wide association studies (GWASs) of large cohorts of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing.

Objectives The authors hypothesise that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci.

Methods The authors performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity haplotype (RCHHs). Weights were constructed based on the frequency of these RCHHs in case versus controls, and used to adjust the p values from a large collaborative GWAS of COPD.

Results The authors identified 2318 RCHHs, of which 576 were significantly (p<0.05) over-represented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, the authors identified two single nucleotide polymorphisms (SNPs) in a novel gene (fibroblast growth factor-7 (FGF7)) that gained genome-wide significance by the false discovery rate method. In a follow-up analysis, both SNPs (rs12591300 and rs4480740) were significantly associated with COPD in an independent population (combined p values of 7.9E–7 and 2.8E–6, respectively). In another independent population, increased lung tissue FGF7 expression was associated with worse measures of lung function.

Conclusion Weights constructed from a homozygosity haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on a separate population. This method can be used to identify promising candidate genes that fail to meet strict correction for multiple testing.

https://doi.org/10.1136/thoraxjnl-2011-200017

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    Footnotes

    • Funding The Genetic Epidemiology of COPD in Costa Rica is supported by grant R01HL073373 from the National Heart, Lung, and Blood Institute. The National Emphysema Treatment Trial (NETT) is supported by contracts with the National Heart, Lung, and Blood Institute (N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01HR76119), the Centers for Medicare and Medicaid Services (CMS) and the Agency for Healthcare Research and Quality (AHRQ). The Norway cohort and the ECLIPSE study (http://clinicaltrials.gov identifier NCT00292552; GSK Code SCO104960) are funded by GlaxoSmithKline. The Lovelace Smokers Cohort is supported by funding from the State of New Mexico (appropriation from the Tobacco Settlement Fund) and by grant RO1 ES015482 from the National Institute of Environmental Health Sciences. We acknowledge use of genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02.

    • Competing interests None.

    • Ethics approval Institutional Review Board of University of Pittsburgh, Partners Health Care (Boston), participating NETT centres, Boston VA, Norway, Costa Rica, and Lovelace Respiratory Institute.

    • Provenance and peer review Not commissioned; externally peer reviewed.