CTEPH has shared and distinct genetic associations with pulmonary embolism in a genome-wide association study

Background Chronic Thromboembolic Pulmonary Hypertension (CTEPH) involves formation and non-resolution of thrombus, dysregulated inflammation, angiogenesis and the development of a small vessel vasculopathy. We aimed to establish the genetic basis of CTEPH to gain insight into these pathophysiological contributors. Methods We conducted a genome-wide association study (GWAS) on 1945 European cases and 10491 European controls. We co-analysed our results from CTEPH with existing results from GWAS on deep vein thrombosis (DVT), pulmonary embolism (PE) and idiopathic PAH (IPAH). Findings Our primary GWAS revealed genetic associations at the ABO, FGG, TAP2, F2, and TSPAN15 loci. Through levered analysis with DVT and PE we demonstrate further CTEPH associations at the F11, EDEM2, SLC44A2 and F5 loci but find no statistically significant associations shared with IPAH. Interpretation CTEPH is a partially heritable polygenic disease, with related though distinct genetic associations to PE and to DVT. The genetic associations at TAP2 suggest a potential autoimmune component in CTEPH pathology, and the differential effect size of the F5 association in CTEPH compared to PE/DVT, suggests a lower risk of F5 polymorphisms in CTEPH. Funding This study was supported by the NIHR cardiorespiratory BRC and an unrestricted grant from Bayer Pharmaceuticals ### Competing Interest Statement CR reports grants, personal fees for lectures, steering committee and advisory board work, and non-financial support for meeting attendance from Actelion, personal fees for lectures and advisory board work from Bayer and MSD, personal fees for advisory board work from GSK, outside the submitted work. MW reports personal fees from GSK and Johnson & Johnson/Actelion, outside the submitted work. JPZ received modest fees for research grant, support to travel to meetings and honoraria from Actelion, Bayer, GlaxoSmithKline and Merck Sharp & Dohme MT reports personal fees from GSK, grants and personal fees from J&J/Actelion, grants from Merck and Bayer, outside the submitted work. ### Funding Statement This study was supported by the NIHR cardiorespiratory BRC and an unrestricted grant from Bayer Pharmaceuticals ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK National Health Service Research Ethics Committee of Cambridge East gave ethical approval for this work (REC no. 08/H0802/32 and 08/H0304/56). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes GWAS summary statistics from this article are available upon reasonable request to the authors.