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 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=15 889). 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.
Abstract
Mendelian randomisation using genetic data from the largest-to-date PAH cohort does not support red cell distribution width or iron deficiency as a cause of PAH, which is important when interpreting iron replacement trials in this condition http://bit.ly/2PPaa88
Footnotes
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Conflict of interest: A. Ulrich has nothing to disclose.
Conflict of interest: J. Wharton has nothing to disclose.
Conflict of interest: T.E. Thayer has nothing to disclose.
Conflict of interest: E.M. Swietlik has nothing to disclose.
Conflict of interest: T.R. Assad has nothing to disclose.
Conflict of interest: A.A. Desai has nothing to disclose.
Conflict of interest: S. Gräf has nothing to disclose.
Conflict of interest: L. Harbaum has nothing to disclose.
Conflict of interest: M. Humbert reports grants and personal fees from Bayer and GSK, personal fees from Actelion, Merck and from United Therapeutics, outside the submitted work.
Conflict of interest: N.W. Morrell reports personal fees from Actelion and Morphogen-IX, outside the submitted work.
Conflict of interest: W.C. Nichols has nothing to disclose.
Conflict of interest: F. Soubrier has nothing to disclose.
Conflict of interest: L. Southgate has nothing to disclose.
Conflict of interest: D-A. Trégouët has nothing to disclose.
Conflict of interest: 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.
Conflict of interest: E.L. Brittain reports personal fees for advisory board work from Bayer, outside the submitted work.
Conflict of interest: M.R. Wilkins reports grants from Vifor Pharma, outside the submitted work.
Conflict of interest: I. Prokopenko has nothing to disclose.
Conflict of interest: C.J. Rhodes reports personal fees from Actelion, outside the submitted work.
Support statement: 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.
- Received July 25, 2019.
- Accepted October 29, 2019.
- Copyright ©ERS 2020
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