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

中文翻译：

---

肺动脉高压红细胞分布宽度的孟德尔随机化分析

肺动脉高压 (PAH) 是一种罕见的疾病，可导致右心衰竭过早死亡。它与升高的红细胞分布宽度 (RDW) 密切相关，这是几种铁状态生物标志物的相关性。高 RDW 值可能表明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。应用两样本孟德尔随机化 (MR) 方法来研究对较高 RDW 水平的遗传易感性是否会增加发生 PAH 的几率。主要和次要 MR 分析分别使用所有可用的全基因组显着 RDW 变异（n = 179）和五个通过全身铁状态起作用的全基因组显着 RDW 变异进行。我们证实了观察到的 RDW 和 PAH 之间的关联（OR 1.90，95% CI 1.80–2。01) 在一项多中心病例对照研究中（病例 n=642，疾病对照 n=15889）。根据 RDW 全基因组关联研究中报告的估计值或我们自己的数据，主要 MR 分析有足够的效力来检测 1.25 和 1.52 或更大之间的因果效应（优势比）。在主要 (ORcausal 1.07, 95% CI 0.92–1.24) 或次要 (ORcausal 1.09, 95% CI 0.77–1.54) MR 分析中，没有证据表明 RDW 和 PAH 之间存在因果关系。结果表明，至少一些观察到的 RDW 与 PAH 的关联是继发于疾病进展的。PAH 中铁治疗试验的结果应谨慎解释，因为观察到的任何改善可能与 PAH 的发展没有机械联系。