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

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 (OR _causal 1.07, 95% CI 0.92-1.24) or the secondary (OR _causal 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.
Competing Interests: 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.
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