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

BackgroundChronic 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. MethodsWe 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). FindingsOur 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. InterpretationCTEPH 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. FundingThis study was supported by the NIHR cardiorespiratory BRC and an unrestricted grant from Bayer Pharmaceuticals Research in context Evidence before this studyThis study is the first genome-wide association study (GWAS) in Chronic Thromboembolic Pulmonary Hypertension (CTEPH). There is some existing evidence for genetic associations in the disease: a European study found an increased CTEPH risk in non-O blood groups and large GWAS have been conducted on CTEPH-related diseases pulmonary embolism (PE) and deep vein thrombosis (DVT). A literature review (MedLine and Google Scholar; 14 Dec 2020) using the keywords Chronic Thomboembolic Pulmonary Hypertensions or CTEPH and genetic showed that no other genetic associations with CTEPH have been reported at genome-wide significance (p < 5 x 10-8). Added value of this studyThis study reports several new genetic associations with CTEPH, and identifies similarities and differences between the genetic architectures of CTEPH and DVT/PE. Shared and differential genetic associations between CTEPH and DVT/PE may lead to insights into disease pathobiology and help in developing the potential for use of genetic markers in CTEPH risk prediction Implications of all the available evidenceCTEPH is associated with multiple genetic variants that include ABO, variants adjacent to the FGG, TAP2, TSPAN15, F2, F5/NME7, F11, SLC44A2 and EDEM2 genes. CTEPH has a similar but not identical genetic architecture to PE and to DVT. There is no evidence of shared genetic architecture with idiopathic pulmonary arterial hypertension.