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.
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- Received July 25, 2019.
- Accepted October 29, 2019.
- Copyright ©ERS 2019
