TY - JOUR
T1 - Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension
AU - Ulrich, Anna
AU - Wharton, John
AU - Thayer, Timothy E.
AU - Swietlik, Emilia M.
AU - Assad, Tufik R.
AU - Desai, Ankit A.
AU - Gräf, Stefan
AU - Harbaum, Lars
AU - Humbert, Marc
AU - Morrell, Nicholas W.
AU - Nichols, William C.
AU - Soubrier, Florent
AU - Southgate, Laura
AU - Trégouët, David Alexandre
AU - Trembath, Richard C.
AU - Brittain, Evan L.
AU - Wilkins, Martin R.
AU - Prokopenko, Inga
AU - Rhodes, Christopher J.
N1 - Funding Information:
Acknowledgements: We gratefully acknowledge the participation of patients recruited to the UK National Institute of Health Research BioResource – Rare Diseases (NIHR BR-RD) Study, the UK National Cohort of Idiopathic and Heritable PAH, and the National Institutes of Health/National Heart, Lung, and Blood Institute-sponsored National Biological Sample and Data Repository for PAH (aka PAH Biobank). We thank the physicians, research nurses and coordinators in the UK, Europe and at the 38 pulmonary hypertension centres across the USA involved in the PAH Biobank (www.pahbiobank.org).
Funding Information:
Conflict of interest: A. Ulrich has nothing to disclose. J. Wharton has nothing to disclose. T.E. Thayer has nothing to disclose. E.M. Swietlik has nothing to disclose. T.R. Assad has nothing to disclose. A.A. Desai has nothing to disclose. S. Gräf has nothing to disclose. L. Harbaum has nothing to disclose. M. Humbert reports grants and personal fees from Bayer and GSK, personal fees from Actelion, Merck and from United Therapeutics, outside the submitted work. N.W. Morrell reports personal fees from Actelion and Morphogen-IX, outside the submitted work. W.C. Nichols has nothing to disclose. F. Soubrier has nothing to disclose. L. Southgate has nothing to disclose. D-A. Trégouët has nothing to disclose. R.C. Trembath reports personal fees for advisory board work from Ipsen Pharmaceuticals, personal fees for non-executive board membership from King’s College Hospital NHS Foundation Trust, outside the submitted work. E.L. Brittain reports personal fees for advisory board work from Bayer, outside the submitted work. M.R. Wilkins reports grants from Vifor Pharma, outside the submitted work. I. Prokopenko has nothing to disclose. C.J. Rhodes reports personal fees from Actelion, outside the submitted work.
Funding Information:
The work cited here is supported by funding from the NIHR BR-RD, the British Heart Foundation (SP/12/12/29836), the BHF Cambridge and Imperial Centres of Cardiovascular Research Excellence (RE/18/4/34215), UK Medical Research Council (MR/K020919/1), the Dinosaur Trust, and BHF Programme grants to R.C. Trembath (RG/08/006/25302), N.W. Morrell (RG/13/4/30107) and M.R. Wilkins (RG/10/16/28575). Funding for the PAH Biobank is provided by NIH/NHLBI HL105333. Vanderbilt University Medical Center?s BioVU is supported by numerous sources: institutional funding, private agencies, and federal grants that include the NIH funded Shared Instrumentation Grant S10RR025141; and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vanderbilt.edu/pub/biovu/. E.L. Brittain receives funding from the NIH R01 HL146588, American Heart Association Fellow to Faculty Grant (13FTF16070002) and the Gilead PAH Scholars Award Program. The genotyping of the VESPA samples was supported by RC2GM092618. The authors acknowledge use of BRC Core Facilities provided by the financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Imperial College NHS Trust, Cambridge University Hospitals and Guy?s and St Thomas? NHS Foundation Trust in partnership with King?s College London and King?s College Hospital NHS Foundation Trust and by NIHR funding to the Imperial NIHR Clinical Research Facility. C.J. Rhodes is supported by a British Heart Foundation Intermediate Basic Science Research Fellowship (FS/15/59/31839). L. Southgate is supported by the Wellcome Trust Institutional Strategic Support Fund (204809/Z/16/Z) awarded to St George?s, University of London. I. Prokopenko is supported by the Wellcome Trust (WT205915), and the EU H2020 (DYNAhealth, project number 633595). N.W. Morrell is a British Heart Foundation Professor and National Institute of Health Research (NIHR) Senior Investigator. W.C. Nichols is supported by NIH NHLBI HL105333. A.A. Desai receives support from NIH NHLBI R01HL136603. Funding information for this article has been deposited with the Crossref Funder Registry.
Publisher Copyright:
Copyright © ERS 2020.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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 whether 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 multicentre case–control study (cases n=642, disease controls n=15889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study 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.
AB - 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 whether 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 multicentre case–control study (cases n=642, disease controls n=15889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study 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.
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U2 - 10.1183/13993003.01486-2019
DO - 10.1183/13993003.01486-2019
M3 - Article
C2 - 31744833
AN - SCOPUS:85079350130
VL - 55
JO - Scandinavian Journal of Respiratory Diseases
JF - Scandinavian Journal of Respiratory Diseases
SN - 0903-1936
IS - 2
M1 - 1901486
ER -