Genetic investigations of causality in disease applied to iron deficiency in pulmonary arterial hypertension
Creators: name: Ulrich, Anna
Publisher: name: Imperial College London
Year: 2020

description: Idiopathic pulmonary arterial hypertension (IPAH) is a rare and devastating disease with poor prognosis and high mortality despite novel therapeutic options. Iron deficiency is a therapeutic target of interest in IPAH, given its prevalence and association with outcomes, the promising results of open label studies of iron replacement in IPAH patients and the physiological link between iron availability and the response to hypoxia in healthy individuals. To date, evidence of a causal relationship between iron deficiency and IPAH is lacking. Epidemiological investigation into the prevalence and prognostic value of iron availability in a etiologically heterogenous cohort of pulmonary hypertension (PH) patients including IPAH showed that iron deficiency is common in all PH etiologies as well as disease controls referred to the PH clinic at Hammersmith Hospital. Distinct definitions of iron deficiency associated with varying outcomes in patients highlight the difficulty in correctly identifying iron deficiency in chronic diseases and calls for the evaluation of iron status biomarkers in PH. Mendelian Randomisation (MR) analysis of iron availability via red cell distribution width (RDW) and IPAH susceptibility did not provide evidence for a causal relationship between iron status and IPAH susceptibility. Secondary MR analysis using instrumental RDW loci acting through systemic iron status also did not support a causal association. Both analyses were well powered to detect a causal effect estimated by the observational study although a more modest causal effect, similar to MR estimates previously reported between iron status and other diseases, cannot be ruled out. The MR analysis of iron status and IPAH is in line with the results of the first cross-over randomized controlled trial (RCT) of iron supplementation in IPAH patients with iron deficiency. Single infusion of ferric carboxymaltose (1000 mg) was well tolerated and restored iron stores to iron replete levels in 62% of IPAH patients. No effect of iron treatment was found on either primary or secondary outcomes. Secondary analyses found no effect of the magnitude of improvement in iron availability on change in disease severity and exercise measures from baseline to 12 weeks. The conclusions from these two approaches (MR and RCT) suggest that iron deficiency is not a powerful therapeutic target in PAH and therefore not a priority for future clinical studies. Genome- and transcriptome-wide eQTL-mapping in a cohort of IPAH patients identified hundreds of potentially novel expression quantitative trait loci (eQTL) colocalizing with twice the proportion of GWAS loci for lung-related phenotypes than eQTL validated by population-based studies. Apart from pulmonary conditions, these novel eQTL specific to or active in PAH could be useful in understanding genetic risk factors for other diseases that share common mechanisms with PAH, such as those with immune dysregulation. The use of genetic epidemiology to investigate causal relationships and assess the genetic architecture shared between PAH and other candidate phenotypes could lead to improved understanding of PAH mechanisms and identify PAH risk factors and potential therapeutic targets. Such analyses will be made more powerful by increasing the accuracy of PAH genetic effect estimates through extensive collaboration, and by improving QTL definitions of phenotypes relevant to PAH.