Genetic determinants of risk and survival in pulmonary arterial hypertension
Authors: Rhodes Christopher J. , Batai Ken , Bleda Marta , Haimel Matthias , Southgate Laura , Germain Marine , Pauciulo Michael W. , Hadinnapola Charaka , Aman Jurjan , Girerd Barbara , Arora Amit , Knight Jo , Hanscombe Ken B. , Karnes Jason H. , Kaakinen Marika , Gall Henning , Ulrich Anna , Harbaum Lars , Cebola Inês , Ferrer Jorge ,   The NIHR BioResource – Rare Diseases Consortium UK PAH Cohort Study Consortium and the US PAH Biobank Consortium,, Ahmad Ferhaan , Amouyel Philippe , Stephen L. Archer , Argula Rahul , Eric D. Austin , Badesch David , Bakshi Sahil , Barnett Christopher F. , Benza Raymond , Bhatt Nitin , Bogaard Harm J. , Burger Charles D. , Chakinala Murali M. , Church Colin , Coghlan John G. , Condliffe Robin , Corris Paul A. , Danesino Cesare , Debette Stéphanie , Elliott C. Gregory , Elwing Jean , Eyries Melanie , Fortin Terry , Franke Andre , Frantz Robert P. , Frost Adaani , Garcia Joe G.N. , Ghio Stefano , Ghofrani Hossein-Ardeschir , Simon J. , Gibbs R. , Harley John B. , He Hua , Hill Nicholas S. , Hirsch Russel , Houweling Arjan C. , Howard Luke S. , Ivy Dunbar , Kiely David G. , Klinger James , Kovacs Gabor , Lahm Tim , Laudes Matthias , Lutz Katie , Machado Rajiv D. , MacKenzie Ross Robert V. , Marsolo Keith , Martin Lisa J. , Moledina Shahin , Montani David , Nathan Steven D. , Newnham Michael , Olschewski Andrea , Olschewski Horst , Oudiz Ronald J. , Ouwehand Willem H. , Peacock Andrew J. , Pepke-Zaba Joanna , Rehman Zia , Robbins Ivan M. , Roden Dan M. , Rosenzweig Erika B. , Saydain Ghulam , Scelsi Laura , Schilz Robert , Seeger Werner , Shaffer Christian M. , Simms Robert W. , Simon Marc , Sitbon Olivier , Suntharalingam Jay , Swietlik Emilia , Tang Haiyang , Tchourbanov Alexander Y. , Thenappan Thenappan , Torres Fernando , Toshner Mark R. , Treacy Carmen M. , Noordegraaf Anton Vonk , Waisfisz Quinten , Walsworth Anna K. , Walter Robert E , Wharton John , White R. James , Wilt Jeffrey , Wort Stephen J. , Yung Delphine , Lawrie Allan , Humbert Marc , Soubrier Florent , Trégouët David-Alexandre , Prokopenko Inga , Kittles Richard , Gräf Stefan , Nichols William C. , Trembath Richard C. , Desai Ankit A. , Morrell Nicholas W. , Wilkins Martin R. 
Published: May 2018

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 atHLA-DPA1/DPB1within the class II major histocompatibility (MHC) region and a second nearSOX17were significantly associated with PAH. TheSOX17locus contained two independent signals associated with PAH. Functional and epigenomic data indicate that the risk variants nearSOX17alter gene regulation via an enhancer active in endothelial cells. PAH risk variants determined haplotype-specific enhancer activity and CRISPR-inhibition of the enhancer reducedSOX17expression. Analysis of median survival showed that PAH patients with two copies of theHLA-DPA1/DPB1risk 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 inHLA-DPA1/DPB1and an enhancer nearSOX17are associated with PAH. Impairment of Sox17 function may be more common in PAH than suggested by rare mutations inSOX17. Allelic variation atHLA-DPB1stratifies 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.