Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Background: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10 –15 ) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10 –20 ) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10 –12 ; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. 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.

Original languageEnglish (US)
Pages (from-to)227-238
Number of pages12
JournalThe Lancet Respiratory Medicine
Volume7
Issue number3
DOIs
StatePublished - Mar 2019

Bibliographical note

Funding Information:
CJR reports personal fees from Actelion Pharmaceuticals. HG reports personal fees and non-financial support from Actelion, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline (GSK), Janssen Cilag, Lilly, Merck Sharp & Dohme (MSD), Novartis, Pfizer, and United Therapeutics/OMT. KL reports grants from the US National Institutes of Health (NIH). FA reports grants from NIH. PA reports personal fees from Servier, Total, Genoscreen, Takeda, and Foundation Plan Alzheimer. RA is on the advisory boards of Actelion Pharmaceuticals and Gilead Pharmaceuticals, and reports grants from Reata Pharmaceuticals. DB reports grants from NIH/National Heart, Lung, and Blood Institute (NHLBI) subcontract through the University of Cincinnati (Cincinnati, OH, USA); grants and personal fees from Acceleron, Actelion, Gilead, United Therapeutics/Lung LLC, Arena, Liquidia, Complexa, Bayer, and Bellerophon; personal fees from Respira; and grants from Novartis. MC reports grants and personal fees from Actelion, Bayer, Gilead, United Therapeutics, and Reata; grants from Eiger, Medtronic, Novartis, and Liquidia; personal fees from Express Scripts, Phase Bio, WebMD Medscape, and SteadyMed; salary support for continuing medical education review from Pulmonary Hypertension Association; and grants from NIH. RC reports personal fees from Actelion, MSD, and Bayer. PAC reports grants and personal fees from Bayer and Actelion, and personal fees from MSD. CGE reports grants from Intermountain Healthcare and Actelion; consultant fees paid by Intermountain Healthcare (event adjudication committee for BEAT study) from Lung Biotechnology; safety committee board fees from ARENA; and data safety monitoring board fees from Actelion. TF reports grants and personal fees from Gilead and United Therapeutics; and grants from Actelion, Lungs Rx, Bayer, and Eiger. RPF reports grants from NIH/NHLBI. H-AG reports personal fees from Actelion, Bayer, GSK, Novartis, Pfizer, Bellerophon Pulse Technologies, and MSD; and grants from Deutsche Forschungsgemeinschaft. JSRG reports grants and personal fees from Actelion, Bayer, GSK, and MSD; personal fees from Arena, Bellerophon, Complexa, and Pfizer; and grants from United Therapeutics and Amco. JH reports grants from NIH and the US Department of Veterans Affairs; personal fees from Janssen Pharmaceuticals, Shenzhen Rheumatic Disease Hospital (Shenzhen, China), Columbia University (NY, USA), and New York University (NY, USA); and options from Board of Directors service from Now Diagnostics. NSH reports financial support in the form of a subcontract from an NIH grant to the institution to support infrastructure. DI is a consultant for Actelion, Bayer, Lilly, and United Therapeutics through University of Colorado (Aurora, CO, USA) contracts, and reports grant funding from the NIH and US Food and Drug Administration. DGK reports grants, personal fees, and non-financial support from Actelion, Bayer, GSK, and MSD. GK reports personal fees and non-financial support from Actelion, Bayer, GSK, MSD, Pfizer, AOP, Boehringer Ingelheim, Novartis, and Chiesi. TL reports consultancy fees from Actelion, Bayer, and Gilead. MN reports educational travel grants from MSD and GSK. HO reports grants from Bayer, Unither Pharmaceuticals, Actelion Pharmaceuticals, Roche, Boehringer Ingelheim, and Pfizer; personal fees from Gilead Sciences, Encysive Pharmaceuticals, and Nebu-Tec; and personal fees and non-financial support from Bayer, Unither Pharmaceuticals, Actelion Pharmaceuticals, Pfizer, Eli Lilly, Novartis, AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, MSD, and GSK. AJP reports grants and personal fees from Actelion and Bayer; personal fees from GSK and Pfizer; and grants from Gilead. JP-Z or her institution has received research or educational grants, and she has served on the advisory boards of Actelion, Merck, Bayer, and GSK. GS reports grants from NIH; grants and non-financial support from Actelion; and personal fees from Bayer and Gilead. RS is on the speakers’ bureau and has done funded clinical research or consulting for Actelion, Bayer, Gilead, Arena, Eiger, and United Therapeutics. WS reports personal fees from United Therapeutics, Liquidia Technologies, and Bayer AG. MS reports grants from NIH/Cincinnati Children's Hospital Medical Center, NIH, US National Science Foundation, Aires/Mast Therapeutics, Novartis; and personal fees from United Therapeutics, Gilead, Actelion, Bayer, St Jude Medical, Hovione, and Complexa. TT reports personal fees from Actelion and Gilead. FT reports grants from United Therapeutics, Gilead, Medtronic, Eiger, and GeNO; and personal fees from Actelion, Bayer Pharmaceuticals, SteadyMed, Reata, Arena, and Bellerophon. AKW reports grants from NIH. JWh reports personal fees from Actelion Pharmaceuticals. RJW reports grants from NIH/NHLBI. SJW reports grants and personal fees from Actelion Pharmaceuticals and Bayer, and personal fees from MSD and GSK. WCN reports grants from NIH. All other authors declare no competing interests.

Funding Information:
We gratefully acknowledge the participation of patients recruited to the UK National Institute of Health Research BioResource (NIHRBR) Rare Diseases study. We thank the NIHRBR staff and coordination teams at the University of Cambridge (Cambridge, UK), and the research nurses and coordinators at the specialist pulmonary hypertension centres involved in this study. We are also grateful to Jenny Thomson and Caroline Langman for invaluable assistance in patient recruitment for the British Heart Foundation Pulmonary Arterial Hypertension (BHFPAH) study. The UK National Cohort of Idiopathic and Heritable PAH is supported by the NIHRBR; the BHF ( SP/12/12/29836 ); the BHF Cambridge Centre of Cardiovascular Research Excellence; the UK Medical Research Council ( MR/K020919/1 ); the Dinosaur Trust; BHF Programme grants to RCT ( RG/08/006/25302 ), NWM ( RG/13/4/30107 ), and MRW ( RG/10/16/28575 ). We also gratefully acknowledge the participation of patients recruited to the US National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)-sponsored National Biological Sample and Data Repository for PAH (also known as PAH Biobank). We thank the physicians, research nurses, and coordinators at the 38 pulmonary hypertension centres across the USA involved in the PAH Biobank. Vanderbilt University Medical Center's BioVU projects are supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141 ; and CTSA grants UL1TR002243 , UL1TR000445 , and UL1RR024975 . The genotyping of the VESPA samples was supported by RC2GM092618. The authors acknowledge use of BRC Core Facilities provided by financial support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Cambridge Biomedical Research Centre, Imperial College Healthcare NHS Trust, and Guy's and St Thomas’ NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. NWM is a British Heart Foundation Professor and NIHR Senior Investigator. CH is a NIHR Rare Disease Translational Research Collaboration Clinical PhD Fellow. CJR is supported by a BHF Intermediate Basic Science Research fellowship ( FS/15/59/31839 ). LH and JA are the recipients of ERS and joint ERS/EMBO Long-Term Research Fellowships (LTRF 2016–6884 and LTRF 201701-00072 ). AL is supported by a BHF Senior Basic Science Research fellowship ( FS/13/48/30453 ). LSo is supported by the Wellcome Trust Institutional Strategic Support Fund ( 204809/Z/16/Z ) awarded to St George's, University of London (London, UK). IP is supported by the Wellcome Trust (WT205915 ), and the EU H2020 programme (DYNAhealth, project number 633595 ). Funding for the PAH Biobank is provided by NIH/NHLBI ( HL105333 ). WCN and MWP are supported by NIH/NHLBI ( HL105333 ). JHK receives support from the American Heart Association ( 16SDG29090005 ) and the American College of Clinical Pharmacy Research Institute (Futures Grant). AAD receives support from NIH/NHLBI ( R01HL136603 ). JF is supported by the Wellcome Trust ( WT101033 ). JH is supported by eMERGE U01 (NHGRI U01 HG008666 ). We acknowledge the support of the Imperial NIHR Clinical Research Facility and Biomedical Research Centre, Netherlands CardioVascular Research Initiative, the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences. This work was supported in part by the Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, and Agence Nationale de la Recherche (Département Hospitalo-Universitaire Thorax Innovation; LabEx LERMIT, ANR-10-LABX-0033 ; and RHU BIO-ART LUNG 2020 , ANR-15-RHUS-0002 ). MRW and H-AG receive funding from German Research Foundation (DFG) SFB1213 , project A09. The popgen 2.0 network is supported by a grant from the German Ministry for Education and Research ( 01EY1103 ). We thank all the patients and their families who contributed to this research and the UK Pulmonary Hypertension Association for their support.

Publisher Copyright:
© 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

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