Evidence map›Paper›PMID 24429156›Full record

ArticleThe Lancet. Respiratory medicine2013

Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study.

Imre Noth, Yingze Zhang, Shwu-Fan Ma, Carlos Flores, Mathew Barber, Yong Huang, Steven M Broderick, Michael S Wade, Pirro Hysi, Joseph Scuirba and 11 more

Abstract readComparative StudyMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Article in The Lancet. Respiratory medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 354 papers, 12 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
354citing papers in PubMed, 12 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

354 citing papers in PubMed, 12 syntheses or guidelines pooled it.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Pooled it
  5. Common single nucleotide polymorphisms associated with idiopathic pulmonary fibrosis: a systematic review.European respiratory review : an official journal of the European Respiratory Society · 2024
    Pooled it
  6. Pooled it
  7. Pooled it
  8. Pooled it
  9. RMD open · 2022
    Pooled it
  10. Guideline
  11. Pooled it
  12. Pooled it
  13. Article
  14. Article
  15. Article
  16. Review
  17. Prevalence and Prognostic Impact of Progressive Pulmonary Fibrosis.Tuberculosis and respiratory diseases · 2026
    Review
  18. Article
  19. Article
  20. Article

294 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

21 authors.

Imre Noth *Section of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Yingze Zhang *Section of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Shwu-Fan Ma *Section of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Carlos FloresSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Mathew BarberSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Yong HuangSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Steven M BroderickSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Michael S WadeSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Pirro HysiSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Joseph ScuirbaSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Thomas J RichardsSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Brenda M Juan-GuardelaSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Rekha VijSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
MeiLan K HanSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Fernando J MartinezSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Karl KossenSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Scott D SeiwertSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Jason D ChristieSection of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Dan Nicolae *Section of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Naftali Kaminski *Section of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).
Joe G N Garcia *Section of Pulmonary and Critical Care Medicine (Prof I Noth MD, S-F Ma PhD, M Barber PhD, Y Huang MS, S M Broderick BS, R Vij MD) and Section of Genetic Medicine (Prof D Nicolae PhD), University of Chicago, Chicago, IL, USA; Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (Y Zhang PhD, J Scuirba BS, T J Richards PhD, B M Juan-Guardela MD, Prof N Kaminski MD); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (C Flores PhD); Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain (C Flores); Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL, USA (M S Wade MS, Prof J G N Garcia MD); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (P Hysi PhD); Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA (M K Han MD, Prof F J Martinez MD); InterMune, Brisbane, CA, USA (K Kossen PhD, S D Seiwert PhD); and Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Pennsylvania, PA, USA (J D Christie MD).

Funding

TRANSLATIONAL RESEARCH UNIVERSITY OF CHICAGO: CLINICAL TRIALSUL1RR024999 · NCRR · UNIVERSITY OF CHICAGO · PI SOLWAY, JULIAN · 2007 to 2011
$25.3M
Therapeutic Potential of FTY720 Analogues in Lung InjuryP01HL098050 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI NATARAJAN, VISWANATHAN · 2011 to 2015
$10.9M
CTRIP: Molecular phenotypes of rapidly progressive idiopathic pulmonary fibrosisRC2HL101740 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI FLAHERTY, KEVIN R, MARTINEZ, FERNANDO J · 2009 to 2010
$7.9M
Clinical Risk Factors for Primary Graft DysfunctionR01HL087115 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI CHRISTIE, JASON D · 2007 to 2017
$7.1M
Phase II Study of Inhales Carbon Monoxide for the Treatment of Idiopathic PulmonaU01HL105371 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI GARCIA, JOE G. N., ROSAS, IVAN O. · 2010 to 2014
$5.2M
Molecular Phenotypes within and across disease boundaries in IPF and COPDR01HL095397 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI KAMINSKI, NAFTALI, SHAPIRO, STEVEN D · 2008 to 2011
$3.0M
Role of anti-Col (V) immunity in primary graft dysfunctionR01HL096845 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI CHRISTIE, JASON D, WILKES, DAVID S · 2010 to 2013
$2.2M
Genome-Wide Association and Exon Sequencing Study in IPFRC1HL099619 · NHLBI · UNIVERSITY OF CHICAGO · PI KAMINSKI, NAFTALI, NICOLAE, DAN LIVIU · 2009 to 2010
$1.0M
Combination Therapy in IPFU10HL080513 · NHLBI · UNIVERSITY OF CHICAGO · PI NOTH, IMRE · 2005 to 2009
$970k
INTEGRINS ON AIRWAY SMOOTH MUSCLE PROLIFERATIONF32HL009961 · NHLBI · UNIVERSITY OF CALIFORNIA SAN FRANCISCO · PI LEE, JUNE H · 1998 to 1999
–
NCRR NIH HHS UL1 RR024999NHLBI NIH HHS F32 HL009961NHLBI NIH HHS HL080513NHLBI NIH HHS HL101740NHLBI NIH HHS P01 HL098050NHLBI NIH HHS P01 HL98050NHLBI NIH HHS P50 HL0894932NHLBI NIH HHS R01 HL087115NHLBI NIH HHS R01 HL095397NHLBI NIH HHS R01 HL096845NHLBI NIH HHS R01 HL1081619NHLBI NIH HHS R01 HL95397NHLBI NIH HHS RC1 HL09961NHLBI NIH HHS RC1 HL099619NHLBI NIH HHS RC2 HL096845NHLBI NIH HHS RC2 HL101740NHLBI NIH HHS U01 HL105371NHLBI NIH HHS U10 HL080513
6 · The paper itself

Abstract

backgroundIdiopathic pulmonary fibrosis (IPF) is a devastating disease that probably involves several genetic loci. Several rare genetic variants and one common single nucleotide polymorphism (SNP) of MUC5B have been associated with the disease. Our aim was to identify additional common variants associated with susceptibility and ultimately mortality in IPF.

methodsFirst, we did a three-stage genome-wide association study (GWAS): stage one was a discovery GWAS; and stages two and three were independent case-control studies. DNA samples from European-American patients with IPF meeting standard criteria were obtained from several US centres for each stage. Data for European-American control individuals for stage one were gathered from the database of genotypes and phenotypes; additional control individuals were recruited at the University of Pittsburgh to increase the number. For controls in stages two and three, we gathered data for additional sex-matched European-American control individuals who had been recruited in another study. DNA samples from patients and from control individuals were genotyped to identify SNPs associated with IPF. SNPs identified in stage one were carried forward to stage two, and those that achieved genome-wide significance (p<5 × 10(-8)) in a meta-analysis were carried forward to stage three. Three case series with follow-up data were selected from stages one and two of the GWAS using samples with follow-up data. Mortality analyses were done in these case series to assess the SNPs associated with IPF that had achieved genome-wide significance in the meta-analysis of stages one and two. Finally, we obtained gene-expression profiling data for lungs of patients with IPF from the Lung Genomics Research Consortium and analysed correlation with SNP genotypes.

findingsIn stage one of the GWAS (542 patients with IPF, 542 control individuals matched one-by-one to cases by genetic ancestry estimates), we identified 20 loci. Six SNPs reached genome-wide significance in stage two (544 patients, 687 control individuals): three TOLLIP SNPs (rs111521887, rs5743894, rs5743890) and one MUC5B SNP (rs35705950) at 11p15.5; one MDGA2 SNP (rs7144383) at 14q21.3; and one SPPL2C SNP (rs17690703) at 17q21.31. Stage three (324 patients, 702 control individuals) confirmed the associations for all these SNPs, except for rs7144383. Linkage disequilibrium between the MUC5B SNP (rs35705950) and TOLLIP SNPs (rs111521887 [r(2)=0·07], rs5743894 [r(2)=0·16], and rs5743890 [r(2)=0·01]) was low. 683 patients from the GWAS were included in the mortality analysis. Individuals who developed IPF despite having the protective TOLLIP minor allele of rs5743890 carried an increased mortality risk (meta-analysis with fixed-effect model: hazard ratio 1·72 [95% CI 1·24-2·38]; p=0·0012). TOLLIP expression was decreased by 20% in individuals carrying the minor allele of rs5743890 (p=0·097), 40% in those with the minor allele of rs111521887 (p=3·0 × 10(-4)), and 50% in those with the minor allele of rs5743894 (p=2·93 × 10(-5)) compared with homozygous carriers of common alleles for these SNPs.

interpretationNovel variants in TOLLIP and SPPL2C are associated with IPF susceptibility. One novel variant of TOLLIP, rs5743890, is also associated with mortality. These associations and the reduced expression of TOLLIP in patients with IPF who carry TOLLIP SNPs emphasise the importance of this gene in the disease.

fundingNational Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III.

Indexed as

Genetic Predisposition to DiseaseGenetic VariationAdultAgedDNAFemaleGenome-Wide Association StudyGenotypeHumansIdiopathic Pulmonary FibrosisLinkage DisequilibriumMaleMiddle AgedPhenotypeRetrospective StudiesSurvival RateDNA

Identifiers

PMID24429156
PMCPMC3894577

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