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Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension

Anna Ulrich, John Wharton, Timothy E. Thayer, Emilia M. Swietlik, Tufik R. Assad, Ankit A. Desai, Stefan Gräf, Lars Harbaum, Marc Humbert, Nicholas W. Morrell, William C. Nichols, Florent Soubrier, Laura Southgate, David-Alexandre Trégouët, Richard C. Trembath, Evan L. Brittain, Martin R. Wilkins, Inga Prokopenko, Christopher J. Rhodes on behalf of The NIHR BioResource – Rare Diseases Consortium, UK PAH Cohort Study Consortium, the US PAH Biobank Consortium
European Respiratory Journal 2019; DOI: 10.1183/13993003.01486-2019
Anna Ulrich
1National Heart and Lung Institute, Hammersmith Campus, Imperial College London, London, United Kingdom
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John Wharton
1National Heart and Lung Institute, Hammersmith Campus, Imperial College London, London, United Kingdom
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Timothy E. Thayer
2Vanderbilt University Medical Center, Division of Cardiovascular Medicine, Nashville, TN, USA
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Emilia M. Swietlik
3Department of Medicine, University of Cambridge, Cambridge, United Kingdom
4Pulmonary Vascular Disease Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
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Tufik R. Assad
5Williamson Country Medical Center, Franklin, TN, USA
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Ankit A. Desai
6Indiana University, Indianapolis, IN, USA
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Stefan Gräf
3Department of Medicine, University of Cambridge, Cambridge, United Kingdom
7NIHR BioResource - Rare Diseases, Cambridge, United Kingdom
8Department of Haematology, University of Cambridge, Cambridge, United Kingdom
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Lars Harbaum
1National Heart and Lung Institute, Hammersmith Campus, Imperial College London, London, United Kingdom
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Marc Humbert
9Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, France
10AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
11INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, Paris, France
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Nicholas W. Morrell
3Department of Medicine, University of Cambridge, Cambridge, United Kingdom
7NIHR BioResource - Rare Diseases, Cambridge, United Kingdom
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William C. Nichols
12Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Florent Soubrier
13Sorbonne Universités, UPMC Univ. Paris 06, Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1166, Paris, France
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Laura Southgate
14Molecular and Clinical Sciences Research Institute, St George's University of London, London, United Kingdom
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David-Alexandre Trégouët
15INSERM UMR_S 1219, Bordeaux Population Health research center, University of Bordeaux, Bordeaux, France
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Richard C. Trembath
16Division of Genetics and Molecular Medicine, King's College London, London, United Kingdom
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Evan L. Brittain
2Vanderbilt University Medical Center, Division of Cardiovascular Medicine, Nashville, TN, USA
17Vanderbilt Translational and Clinical Cardiovascular Research Center, Nashville, TN, USA
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Martin R. Wilkins
1National Heart and Lung Institute, Hammersmith Campus, Imperial College London, London, United Kingdom
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Inga Prokopenko
18Department of Clinical and Experimental Medicine, University of Surrey, Guildford, United Kingdom
19Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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Christopher J. Rhodes
1National Heart and Lung Institute, Hammersmith Campus, Imperial College London, London, United Kingdom
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Abstract

Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early stage iron deficiency or iron deficiency anaemia. This study investigated if elevated RDW is causally associated with PAH.

A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively.

We confirmed the observed association between RDW and PAH (OR=1.90, 95% CI=1.80–2.01) in a multi-centre case-control study (N cases=642, N disease controls=15 889). The primary MR analysis was adequately powered to detect a causal effect (OR) from between 1.25 and 1.52 or greater based on estimates reported in the RDW GWAS or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal=1.07, 95% CI=0.92–1.24) or the secondary (ORcausal=1.09, 95% CI=0.77–1.54) MR analysis.

The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution as any improvements observed may not be mechanistically linked to the development of PAH.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Ulrich has nothing to disclose.

Conflict of interest: Dr. Wharton has nothing to disclose.

Conflict of interest: Dr. Tayer has nothing to disclose.

Conflict of interest: Dr. Swietlik has nothing to disclose.

Conflict of interest: Dr. Assad has nothing to disclose.

Conflict of interest: Dr. Desai has nothing to disclose.

Conflict of interest: Dr. Gräf has nothing to disclose.

Conflict of interest: Dr. Harbaum has nothing to disclose.

Conflict of interest: Dr. Humbert reports personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from Merck, from United Therapeutics, outside the submitted work.

Conflict of interest: Dr. Morrell reports personal fees from Actelion, personal fees from Morphogen-IX, outside the submitted work.

Conflict of interest: Dr. Nichols has nothing to disclose.

Conflict of interest: Dr. SOUBRIER has nothing to disclose.

Conflict of interest: Dr. Southgate has nothing to disclose.

Conflict of interest: Dr. tregouet has nothing to disclose.

Conflict of interest: Dr. Trembath reports personal fees from Ipsen Pharmaceuticals, personal fees from King's College Hospital NHS Foundation Trust, outside the submitted work.

Conflict of interest: Dr. Brittain reports personal fees from Bayer, outside the submitted work.

Conflict of interest: Dr. Wilkins reports grants from Vifor Pharma, outside the submitted work.

Conflict of interest: Dr. Prokopenko has nothing to disclose.

Conflict of interest: Dr. Rhodes reports personal fees from Actelion, outside the submitted work.

This is a PDF-only article. Please click on the PDF link above to read it.

  • Received July 25, 2019.
  • Accepted October 29, 2019.
  • Copyright ©ERS 2019
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Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension
Anna Ulrich, John Wharton, Timothy E. Thayer, Emilia M. Swietlik, Tufik R. Assad, Ankit A. Desai, Stefan Gräf, Lars Harbaum, Marc Humbert, Nicholas W. Morrell, William C. Nichols, Florent Soubrier, Laura Southgate, David-Alexandre Trégouët, Richard C. Trembath, Evan L. Brittain, Martin R. Wilkins, Inga Prokopenko, Christopher J. Rhodes
European Respiratory Journal Jan 2019, 1901486; DOI: 10.1183/13993003.01486-2019

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Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension
Anna Ulrich, John Wharton, Timothy E. Thayer, Emilia M. Swietlik, Tufik R. Assad, Ankit A. Desai, Stefan Gräf, Lars Harbaum, Marc Humbert, Nicholas W. Morrell, William C. Nichols, Florent Soubrier, Laura Southgate, David-Alexandre Trégouët, Richard C. Trembath, Evan L. Brittain, Martin R. Wilkins, Inga Prokopenko, Christopher J. Rhodes
European Respiratory Journal Jan 2019, 1901486; DOI: 10.1183/13993003.01486-2019
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