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

Ulrich, A; Wharton, J; Thayer, TE; Swietlik, EM; Assad, TR; Desai, AA; Gräf, S; Harbaum, L; Humbert, M; Morrell, NW; et al. Ulrich, A; Wharton, J; Thayer, TE; Swietlik, EM; Assad, TR; Desai, AA; Gräf, S; Harbaum, L; Humbert, M; Morrell, NW; Nichols, WC; Soubrier, F; Southgate, L; Trégouët, D-A; Trembath, RC; Brittain, EL; Wilkins, MR; Prokopenko, I; Rhodes, CJ; NIHR BioResource – Rare Diseases Consortium; UK PAH Cohort Study Consortium; US PAH Biobank Consortium (2020) Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension. Eur Respir J, 55 (2). p. 1901486. ISSN 1399-3003 https://doi.org/10.1183/13993003.01486-2019
SGUL Authors: Southgate, Laura

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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.

Item Type: Article
Additional Information: This is an author-submitted, peer-reviewed version of a manuscript that has been accepted for publication in the European Respiratory Journal, prior to copy-editing, formatting and typesetting. This version of the manuscript may not be duplicated or reproduced without prior permission from the copyright owner, the European Respiratory Society. The publisher is not responsible or liable for any errors or omissions in this version of the manuscript or in any version derived from it by any other parties. The final, copy-edited, published article, which is the version of record, is available without a subscription 18 months after the date of issue publication.
Keywords: NIHR BioResource – Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium, 11 Medical And Health Sciences, Respiratory System
Journal or Publication Title: Eur Respir J
ISSN: 1399-3003
Language: eng
Dates:
DateEvent
1 February 2020Published
19 November 2019Published Online
29 October 2019Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
SP/12/12/29836British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RE/18/4/34215British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
MR/K020919/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
RG/08/006/25302British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RG/13/4/30107British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RG/10/16/28575British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
HL105333National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
S10RR025141National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
UL1TR002243National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
UL1TR000445National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
UL1RR024975National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U01HG004798National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01NS032830National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
RC2GM092618National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
P50GM115305National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U01HG006378National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U19HL065962National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01HD074711National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01HL146588National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
13FTF16070002American Heart Associationhttp://dx.doi.org/10.13039/100000968
RC2GM092618National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
FS/15/59/31839British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
204809/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
WT205915Wellcome Trusthttp://dx.doi.org/10.13039/100004440
633595Horizon 2020UNSPECIFIED
HL105333National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01HL136603National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
PubMed ID: 31744833
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111437
Publisher's version: https://doi.org/10.1183/13993003.01486-2019

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