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.
- Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension
- Anna Ulrich - Imperial College LondonJohn Wharton - Imperial College LondonTimothy E. Thayer - Vanderbilt University Medical CenterEmilia M. Swietlik - University of CambridgeTufik R. Assad - Williamson CollegeAnkit A. Desai - Indiana University – Purdue University IndianapolisStefan Graf - University of CambridgeLars Harbaum - Imperial College LondonMarc Humbert - University of Paris-SaclayNicholas W. Morrell - University of CambridgeWilliam C. Nichols - Cincinnati Children's Hospital Medical CenterFlorent Soubrier - InsermLaura Southgate - St George's, University of LondonDavid-Alexandre Tregouet - Bordeaux Population HealthRichard C. Trembath - King's College LondonEvan L. Brittain - Vanderbilt University Medical CenterMartin R. Wilkins - Imperial College LondonInga Prokopenko - University of Surrey, School of BiosciencesChristopher J. Rhodes - Imperial College LondonUS PAH Biobank Consortium
- The European respiratory journal, Vol.55(2), p.1901486
- European Respiratory Soc Journals Ltd
- 9
- 01/02/2020
- NIHR BR-RD SP/12/12/29836 / British Heart Foundation RG/08/006/25302; RG/13/4/30107; RG/10/16/28575 / BHF Programme UL1TR002243; UL1TR000445; UL1RR024975 / CTSA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) RE/18/4/34215 / BHF Cambridge and Imperial Centres of Cardiovascular Research Excellence MR/K020919/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) MR/K020919/1 / UK Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) HL105333 / NIH/NHLBI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01 HL146588; S10RR025141 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- 99817424102346
- School of Biosciences
- English
- Journal article