TY - JOUR T1 - Genetic determinants of risk and survival in pulmonary arterial hypertension JF - bioRxiv DO - 10.1101/317164 SP - 317164 AU - Christopher J. Rhodes AU - Ken Batai AU - Marta Bleda AU - Matthias Haimel AU - Laura Southgate AU - Marine Germain AU - Michael W. Pauciulo AU - Charaka Hadinnapola AU - Jurjan Aman AU - Barbara Girerd AU - Amit Arora AU - Jo Knight AU - Ken B. Hanscombe AU - Jason H. Karnes AU - Marika Kaakinen AU - Henning Gall AU - Anna Ulrich AU - Lars Harbaum AU - Inês Cebola AU - Jorge Ferrer AU - The NIHR BioResource – Rare Diseases Consortium UK PAH Cohort Study Consortium and the US PAH Biobank Consortium, AU - Ferhaan Ahmad AU - Philippe Amouyel AU - Archer Stephen L. AU - Rahul Argula AU - Austin Eric D. AU - David Badesch AU - Sahil Bakshi AU - Christopher F. Barnett AU - Raymond Benza AU - Nitin Bhatt AU - Harm J. Bogaard AU - Charles D. Burger AU - Murali M. Chakinala AU - Colin Church AU - John G. Coghlan AU - Robin Condliffe AU - Paul A. Corris AU - Cesare Danesino AU - Stéphanie Debette AU - C. Gregory Elliott AU - Jean Elwing AU - Melanie Eyries AU - Terry Fortin AU - Andre Franke AU - Robert P. Frantz AU - Adaani Frost AU - Joe G.N. Garcia AU - Stefano Ghio AU - Hossein-Ardeschir Ghofrani AU - J. Simon AU - R. Gibbs AU - John B. Harley AU - Hua He AU - Nicholas S. Hill AU - Russel Hirsch AU - Arjan C. Houweling AU - Luke S. Howard AU - Dunbar Ivy AU - David G. Kiely AU - James Klinger AU - Gabor Kovacs AU - Tim Lahm AU - Matthias Laudes AU - Katie Lutz AU - Rajiv D. Machado AU - Robert V. MacKenzie Ross AU - Keith Marsolo AU - Lisa J. Martin AU - Shahin Moledina AU - David Montani AU - Steven D. Nathan AU - Michael Newnham AU - Andrea Olschewski AU - Horst Olschewski AU - Ronald J. Oudiz AU - Willem H. Ouwehand AU - Andrew J. Peacock AU - Joanna Pepke-Zaba AU - Zia Rehman AU - Ivan M. Robbins AU - Dan M. Roden AU - Erika B. Rosenzweig AU - Ghulam Saydain AU - Laura Scelsi AU - Robert Schilz AU - Werner Seeger AU - Christian M. Shaffer AU - Robert W. Simms AU - Marc Simon AU - Olivier Sitbon AU - Jay Suntharalingam AU - Emilia Swietlik AU - Haiyang Tang AU - Alexander Y. Tchourbanov AU - Thenappan Thenappan AU - Fernando Torres AU - Mark R. Toshner AU - Carmen M. Treacy AU - Anton Vonk Noordegraaf AU - Quinten Waisfisz AU - Anna K. Walsworth AU - Robert E Walter AU - John Wharton AU - R. James White AU - Jeffrey Wilt AU - Stephen J. Wort AU - Delphine Yung AU - Allan Lawrie AU - Marc Humbert AU - Florent Soubrier AU - David-Alexandre Trégouët AU - Inga Prokopenko AU - Richard Kittles AU - Stefan Gräf AU - William C. Nichols AU - Richard C. Trembath AU - Ankit A. Desai AU - Nicholas W. Morrell AU - Martin R. Wilkins Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/05/16/317164.abstract N2 - Background Pulmonary arterial hypertension (PAH) is a rare disorder leading to premature death. Rare genetic variants contribute to disease etiology but the contribution of common genetic variation to disease risk and outcome remains poorly characterized.Methods We performed two separate genome-wide association studies of PAH using data across 11,744 European-ancestry individuals (including 2,085 patients), one with genotypes from 5,895 whole genome sequences and another with genotyping array data from 5,849 further samples. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. We functionally annotated associated variants and tested associations with duration of survival.Findings A locus at HLA-DPA1/DPB1 within the class II major histocompatibility (MHC) region and a second near SOX17 were significantly associated with PAH. The SOX17 locus contained two independent signals associated with PAH. Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. PAH risk variants determined haplotype-specific enhancer activity and CRISPR-inhibition of the enhancer reduced SOX17 expression. Analysis of median survival showed that PAH patients with two copies of the HLA-DPA1/DPB1 risk variant had a two-fold difference (>16 years versus 8 years), compared to patients homozygous for the alternative allele.Interpretation We have found that common genetic variation at loci in HLA-DPA1/DPB1 and an enhancer near SOX17 are associated with PAH. Impairment of Sox17 function may be more common in PAH than suggested by rare mutations in SOX17. Allelic variation at HLA-DPB1 stratifies PAH patients for survival following diagnosis, with implications for future therapeutic trial design.Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, Inserm, Université Paris-Sud, and French ANR. ER -