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Genetic determinants of risk and survival in pulmonary arterial hypertension

By Christopher J. Rhodes, Ken Batai, Marta Bleda, Matthias Haimel, Laura Southgate, Marine Germain, Michael W. Pauciulo, Charaka Hadinnapola, Jurjan Aman, Barbara Girerd, Amit Arora, Jo Knight, Ken B Hanscombe, Jason H. Karnes, Marika Kaakinen, Henning Gall, Anna Ulrich, Lars Harbaum, Inês Cebola, Jorge Ferrer, The NIHR BioResource – Rare Diseases Consortium UK PAH Cohort Study Consortium and the US PAH Biobank Consortium,, Ferhaan Ahmad, Philippe Amouyel, Archer Stephen L., Rahul Argula, Austin Eric D., David Badesch, Sahil Bakshi, Christopher F. Barnett, Raymond Benza, Nitin Bhatt, Harm J. Bogaard, Charles D. Burger, Murali M. Chakinala, Colin Church, John G. Coghlan, Robin Condliffe, Paul A. Corris, Cesare Danesino, Stéphanie Debette, C. Gregory Elliott, Jean Elwing, Melanie Eyries, Terry Fortin, Andre Franke, Robert P. Frantz, Adaani Frost, Joe G.N. Garcia, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon, R. Gibbs, John B. Harley, Hua He, Nicholas S. Hill, Russel Hirsch, Arjan C. Houweling, Luke S. Howard, Dunbar Ivy, David G. Kiely, James Klinger, Gabor Kovacs, Tim Lahm, Matthias Laudes, Katie Lutz, Rajiv D. Machado, Robert V. MacKenzie Ross, Keith Marsolo, Lisa J Martin, Shahin Moledina, David Montani, Steven D. Nathan, Michael Newnham, Andrea Olschewski, Horst Olschewski, Ronald J. Oudiz, Willem H. Ouwehand, Andrew J. Peacock, Joanna Pepke-Zaba, Zia Rehman, Ivan M. Robbins, Dan M. Roden, Erika B. Rosenzweig, Ghulam Saydain, Laura Scelsi, Robert Schilz, Werner Seeger, Christian M. Shaffer, Robert W. Simms, Marc Simon, Olivier Sitbon, Jay Suntharalingam, Emilia Swietlik, Haiyang Tang, Alexander Y. Tchourbanov, Thenappan Thenappan, Fernando Adrian Torres, Mark R. Toshner, Carmen M. Treacy, Anton Vonk Noordegraaf, Quinten Waisfisz, Anna K. Walsworth, Robert E Walter, John Wharton, R. James White, Jeffrey Wilt, Stephen J. Wort, Delphine Yung, Allan Lawrie, Marc Humbert, Florent Soubrier, David-Alexandre Trégouët, Inga Prokopenko, Richard Kittles, Stefan Gräf, William C. Nichols, Richard Trembath, Ankit A Desai, Nicholas W. Morrell, Martin R Wilkins

Posted 16 May 2018
bioRxiv DOI: 10.1101/317164 (published DOI: 10.1016/S2213-2600(18)30409-0)

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, Universite Paris-Sud, and French ANR.

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