Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension
| Autor: | Christopher J. Rhodes, Anna Ulrich, William C. Nichols, Tufik R. Assad, Richard C. Trembath, Martin R. Wilkins, Lars Harbaum, Stefan Gräf, Marc Humbert, David-Alexandre Trégouët, John Wharton, Florent Soubrier, Ankit A. Desai, Nicholas W. Morrell, Inga Prokopenko, Emilia M. Swietlik, Evan L. Brittain, Laura Southgate, Timothy E. Thayer |
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| Přispěvatelé: | British Heart Foundation, The Academy of Medical Sciences, Imperial College London, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], University of Cambridge [UK] (CAM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Cincinnati Children's Hospital Medical Center, Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), St George's, University of London, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), King‘s College London, University of Surrey (UNIS), Gestionnaire, Hal Sorbonne Université, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology
Erythrocyte Indices Pulmonary and Respiratory Medicine medicine.medical_specialty Hypertension Pulmonary NIHR BioResource – Rare Diseases Consortium Respiratory System UK PAH Cohort Study Consortium Disease 030204 cardiovascular system & hematology [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract Gastroenterology 03 medical and health sciences symbols.namesake 0302 clinical medicine Internal medicine medicine Genetic predisposition Humans 030212 general & internal medicine Respiratory system 11 Medical and Health Sciences Pulmonary Vascular Disease Pulmonary Arterial Hypertension business.industry [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology Red blood cell distribution width Original Articles Odds ratio Iron deficiency medicine.disease and the US PAH Biobank Consortium 3. Good health VINTAGE Case-Control Studies Mendelian inheritance symbols [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract business Genome-Wide Association Study Rare disease |
| Zdroj: | The European Respiratory Journal European Respiratory Journal European Respiratory Journal, European Respiratory Society, 2020, 55 (2), pp.1901486. ⟨10.1183/13993003.01486-2019⟩ European Respiratory Journal, 2020, 55 (2), pp.1901486. ⟨10.1183/13993003.01486-2019⟩ |
| ISSN: | 0903-1936 1399-3003 |
| Popis: | 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. 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 |
| Databáze: | OpenAIRE |
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