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

Autor:	Rhodes CJ; Department of Medicine, Imperial College London, London, UK., Batai K; Department of Surgery, University of Arizona, Tucson, AZ, USA., Bleda M; Department of Medicine, University of Cambridge, Cambridge, UK., Haimel M; Department of Medicine, University of Cambridge, Cambridge, UK., Southgate L; Molecular and Clinical Sciences Research Institute, St George's University of London, London, UK., Germain M; Sorbonne Universités, UPMC, INSERM, Paris, France., Pauciulo MW; Human Genetics, Cincinnati, OH, USA., Hadinnapola C; Department of Medicine, University of Cambridge, Cambridge, UK., Aman J; Department of Medicine, Imperial College London, London, UK., Girerd B; University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France., Arora A; Department of Surgery, University of Arizona, Tucson, AZ, USA., Knight J; Data Science Institute, Lancaster University, Lancaster, UK., Hanscombe KB; Genetics and Molecular Medicine, King's College London, London, UK., Karnes JH; Pharmacy Practice and Science, University of Arizona, Tucson, AZ, USA., Kaakinen M; Department of Medicine, Imperial College London, London, UK., Gall H; University of Giessen and Marburg Lung Center, Giessen, Germany., Ulrich A; Department of Medicine, Imperial College London, London, UK., Harbaum L; Department of Medicine, Imperial College London, London, UK., Cebola I; Department of Medicine, Imperial College London, London, UK., Ferrer J; Department of Medicine, Imperial College London, London, UK., Lutz K; Human Genetics, Cincinnati, OH, USA., Swietlik EM; Department of Medicine, University of Cambridge, Cambridge, UK., Ahmad F; University of Iowa, Iowa City, IA, USA., Amouyel P; University of Lille, Lille, France., Archer SL; Queen's University, Kingston, ON, Canada., Argula R; Medical University of South Carolina, Charleston, SC, USA., Austin ED; Vanderbilt University, Nashville, TN, USA., Badesch D; University of Colorado Denver, Denver, CO, USA., Bakshi S; Baylor Research Institute, Plano, TX, USA., Barnett C; Medstar Health, Washington, DC, USA., Benza R; Allegheny-Singer Research Institute, Pittsburgh, PA, USA., Bhatt N; Ohio State University, Columbus, OH, USA., Bogaard HJ; VU University Medical Center, Amsterdam, Netherlands., Burger CD; Mayo Clinic Florida, Jacksonville, FL, USA., Chakinala M; Washington University, St Louis, MO, USA., Church C; Golden Jubilee National Hospital, Glasgow, UK., Coghlan JG; Royal Free Hospital, London, UK., Condliffe R; Royal Hallamshire Hospital, Sheffield, UK., Corris PA; University of Newcastle, Newcastle, UK., Danesino C; University of Pavia, Pavia, Italy., Debette S; University of Bordeaux, Bordeaux, France., Elliott CG; Intermountain Medical Center, Murray, UT, USA., Elwing J; University of Cincinnati, Cincinnati OH, USA., Eyries M; Sorbonne Universités, UPMC, INSERM, Paris, France., Fortin T; Duke University Medical Center, Durham, NC, USA; University of Kiel, Kiel, Germany., Franke A; University of Kiel, Kiel, Germany., Frantz RP; Mayo Clinic, Rochester, MN, USA., Frost A; Houston Methodist Research Institute, Houston, TX, USA., Garcia JGN; Department of Medicine, University of Arizona, Tucson, AZ, USA., Ghio S; Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Ghofrani HA; University of Giessen and Marburg Lung Center, Giessen, Germany., Gibbs JSR; National Heart and Lung Institute, Imperial College London, London, UK., Harley J; CAGE, Cincinnati, OH, USA., He H; Human Genetics, Cincinnati, OH, USA., Hill NS; Tufts-New England Medical Center, Boston, MA, USA., Hirsch R; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; University of Cincinnati, Cincinnati OH, USA., Houweling AC; VU University Medical Center, Amsterdam, Netherlands., Howard LS; National Heart and Lung Institute, Imperial College London, London, UK., Ivy D; Health Sciences Center, University of Colorado, Aurora, CO, USA., Kiely DG; Royal Hallamshire Hospital, Sheffield, UK., Klinger J; Rhode Island Hospital, Providence, RI, USA., Kovacs G; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Lahm T; Indiana University, Indianapolis, IN, USA., Laudes M; University of Kiel, Kiel, Germany., Machado RD; University of Lincoln, Lincoln, UK., MacKenzie Ross RV; Royal United Hospitals Bath NHS Foundation Trust, Bath, UK., Marsolo K; Biomedical Informatics, Cincinnati, OH, USA., Martin LJ; Human Genetics, Cincinnati, OH, USA., Moledina S; Great Ormond Street Hospital, London, UK., Montani D; University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France., Nathan SD; Inova Heart and Vascular Institute, Falls Church, VA, USA., Newnham M; Department of Medicine, University of Cambridge, Cambridge, UK; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Olschewski A; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Olschewski H; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Oudiz RJ; Harbor-UCLA Medical Center, Torrance, CA, USA., Ouwehand WH; Department of Haematology, University of Cambridge, Cambridge, UK., Peacock AJ; Golden Jubilee National Hospital, Glasgow, UK., Pepke-Zaba J; Papworth Hospital, Papworth, UK., Rehman Z; East Carolina University, Greenville, NC, USA., Robbins I; Vanderbilt University School of Medicine, Nashville, TN, USA., Roden DM; Vanderbilt University School of Medicine, Nashville, TN, USA., Rosenzweig EB; Columbia University, New York, NY, USA., Saydain G; Wayne State University, Detroit, MI, USA., Scelsi L; Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Schilz R; University Hospital of Cleveland, Cleveland, OH, USA., Seeger W; University of Giessen and Marburg Lung Center, Giessen, Germany., Shaffer CM; Vanderbilt University School of Medicine, Nashville, TN, USA., Simms RW; Boston University School of Medicine, Boston, MA, USA., Simon M; University of Pittsburgh, Pittsburgh, PA, USA., Sitbon O; University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France., Suntharalingam J; Royal United Hospitals Bath NHS Foundation Trust, Bath, UK., Tang H; Department of Medicine, University of Arizona, Tucson, AZ, USA., Tchourbanov AY; Ambry Genetics, Aliso Viejo, CA, USA., Thenappan T; University of Minnesota, Minneapolis, MN, USA., Torres F; University of Texas Southwestern Medical Center, Dallas, TX, USA., Toshner MR; Department of Medicine, University of Cambridge, Cambridge, UK., Treacy CM; Department of Medicine, University of Cambridge, Cambridge, UK., Vonk Noordegraaf A; VU University Medical Center, Amsterdam, Netherlands., Waisfisz Q; VU University Medical Center, Amsterdam, Netherlands., Walsworth AK; Human Genetics, Cincinnati, OH, USA., Walter RE; Louisiana State University Health, Shreveport, LA, USA., Wharton J; Department of Medicine, Imperial College London, London, UK., White RJ; University of Rochester Medical Center, Rochester, NY, USA., Wilt J; Spectrum Health Hospitals, Grand Rapids, MI, USA., Wort SJ; National Heart and Lung Institute, Imperial College London, London, UK., Yung D; Seattle Children's Hospital, Seattle, WA, USA., Lawrie A; University of Sheffield, Sheffield, UK., Humbert M; University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France., Soubrier F; Sorbonne Universités, UPMC, INSERM, Paris, France., Trégouët DA; Sorbonne Universités, UPMC, INSERM, Paris, France., Prokopenko I; Department of Medicine, Imperial College London, London, UK., Kittles R; City of Hope, Duarte, CA, USA., Gräf S; Department of Medicine, University of Cambridge, Cambridge, UK., Nichols WC; Human Genetics, Cincinnati, OH, USA., Trembath RC; Genetics and Molecular Medicine, King's College London, London, UK., Desai AA; Indiana University, Indianapolis, IN, USA. Electronic address: ankdesai@iu.edu., Morrell NW; Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address: nwm23@cam.ac.uk., Wilkins MR; Department of Medicine, Imperial College London, London, UK. Electronic address: m.wilkins@imperial.ac.uk.
Jazyk:	angličtina
Zdroj:	The Lancet. Respiratory medicine [Lancet Respir Med] 2019 Mar; Vol. 7 (3), pp. 227-238. Date of Electronic Publication: 2018 Dec 05.
DOI:	10.1016/S2213-2600(18)30409-0
Abstrakt:	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. (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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