Shared and Distinct Genomics of Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Embolism
James Liley, Michael Newnham, Marta Bleda, Katherine Bunclark, William R. Auger, Joan Albert Barberà, Harm Jan Bogaard, Marion Delcroix, Timothy M. Fernandes, Luke Howard, David P. Jenkins, Iréne Lang, Eckhard Mayer, Christopher J. Rhodes, Michael A. Simpson, Laura Southgate, Richard C. Trembath, John Wharton, Martin R. Wilkins, Stefan Gräf, Nicholas W. Morrell, Joanna Pepke Zaba, Mark Toshner
Abstract
Abstract Rationale Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. Objectives We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects. We coanalyzed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism, and idiopathic pulmonary arterial hypertension. Measurements and Main Results Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our coanalysis, we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2, and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations with pulmonary embolism and deep vein thrombosis.