Ulrich Anna, Wharton John, Thayer Timothy E, Swietlik Emilia M, Assad Tufik R, Desai Ankit A, Gräf Stefan, Harbaum Lars, Humbert Marc, Morrell Nicholas W, Nichols William C, Soubrier Florent, Southgate Laura, Trégouët David-Alexandre, Trembath Richard C, Brittain Evan L, Wilkins Martin R, Prokopenko Inga, Rhodes Christopher J
National Heart and Lung Institute, Hammersmith Campus, Imperial College London, London, UK.
Vanderbilt University Medical Center, Division of Cardiovascular Medicine, Nashville, TN, USA.
Eur Respir J. 2020 Feb 12;55(2). doi: 10.1183/13993003.01486-2019. Print 2020 Feb.
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 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 1.07, 95% CI 0.92-1.24) or the secondary (OR 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.
肺动脉高压（PAH）是一种罕见疾病，可导致因右心衰竭而过早死亡。它与红细胞分布宽度（RDW）升高密切相关，RDW是几种铁状态生物标志物的一个相关指标。高RDW值可能预示着早期缺铁或缺铁性贫血。本研究调查了RDW升高是否与PAH存在因果关系。采用两样本孟德尔随机化（MR）方法来研究遗传易感性导致的较高水平RDW是否会增加患PAH的几率。分别使用所有可用的全基因组显著RDW变异（n = 179）和五个作用于全身铁状态的全基因组显著RDW变异进行了一级和二级MR分析。
在一项多中心病例对照研究（病例n = 642，疾病对照n = 15889）中，我们证实了观察到的RDW与PAH之间的关联（比值比1.90，95%置信区间1.80 - 2.01）。根据RDW全基因组关联研究报告的估计值或我们自己的数据，一级MR分析有足够的效力检测1.25至1.52或更高的因果效应（比值比）。在一级（比值比1.07，95%置信区间0.92 - 1.24）或二级（比值比1.09，95%置信区间0.77 - 1.54）MR分析中，均没有证据表明RDW与PAH之间存在因果关联。
结果表明，至少部分观察到的RDW与PAH的关联是疾病进展的继发结果。PAH中铁治疗试验的结果应谨慎解读，因为观察到的任何改善可能与PAH的发生机制并无关联。
