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Lancet Respir Med. 2019 Mar;7(3):227-238. doi: 10.1016/S2213-2600(18)30409-0. Epub 2018 Dec 5.

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

Rhodes CJ1, Batai K2, Bleda M3, Haimel M3, Southgate L4, Germain M5, Pauciulo MW6, Hadinnapola C3, Aman J1, Girerd B7, Arora A2, Knight J8, Hanscombe KB9, Karnes JH10, Kaakinen M1, Gall H11, Ulrich A1, Harbaum L1, Cebola I1, Ferrer J1, Lutz K6, Swietlik EM3, Ahmad F12, Amouyel P13, Archer SL14, Argula R15, Austin ED16, Badesch D17, Bakshi S18, Barnett C19, Benza R20, Bhatt N21, Bogaard HJ22, Burger CD23, Chakinala M24, Church C25, Coghlan JG26, Condliffe R27, Corris PA28, Danesino C29, Debette S30, Elliott CG31, Elwing J32, Eyries M5, Fortin T33, Franke A34, Frantz RP35, Frost A36, Garcia JGN37, Ghio S38, Ghofrani HA11, Gibbs JSR39, Harley J40, He H6, Hill NS41, Hirsch R42, Houweling AC22, Howard LS39, Ivy D43, Kiely DG27, Klinger J44, Kovacs G45, Lahm T46, Laudes M34, Machado RD47, MacKenzie Ross RV48, Marsolo K49, Martin LJ6, Moledina S50, Montani D7, Nathan SD51, Newnham M52, Olschewski A45, Olschewski H45, Oudiz RJ53, Ouwehand WH54, Peacock AJ25, Pepke-Zaba J55, Rehman Z56, Robbins I57, Roden DM57, Rosenzweig EB58, Saydain G59, Scelsi L38, Schilz R60, Seeger W11, Shaffer CM57, Simms RW61, Simon M62, Sitbon O7, Suntharalingam J48, Tang H37, Tchourbanov AY63, Thenappan T64, Torres F65, Toshner MR3, Treacy CM3, Vonk Noordegraaf A22, Waisfisz Q22, Walsworth AK6, Walter RE66, Wharton J1, White RJ67, Wilt J68, Wort SJ39, Yung D69, Lawrie A70, Humbert M7, Soubrier F5, Trégouët DA5, Prokopenko I1, Kittles R71, Gräf S3, Nichols WC6, Trembath RC9, Desai AA72, Morrell NW73, Wilkins MR74; UK NIHR BioResource Rare Diseases Consortium; UK PAH Cohort Study Consortium; US PAH Biobank Consortium.

Author information

1
Department of Medicine, Imperial College London, London, UK.
2
Department of Surgery, University of Arizona, Tucson, AZ, USA.
3
Department of Medicine, University of Cambridge, Cambridge, UK.
4
Molecular and Clinical Sciences Research Institute, St George's University of London, London, UK.
5
Sorbonne Universités, UPMC, INSERM, Paris, France.
6
Human Genetics, Cincinnati, OH, USA.
7
University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France.
8
Data Science Institute, Lancaster University, Lancaster, UK.
9
Genetics and Molecular Medicine, King's College London, London, UK.
10
Pharmacy Practice and Science, University of Arizona, Tucson, AZ, USA.
11
University of Giessen and Marburg Lung Center, Giessen, Germany.
12
University of Iowa, Iowa City, IA, USA.
13
University of Lille, Lille, France.
14
Queen's University, Kingston, ON, Canada.
15
Medical University of South Carolina, Charleston, SC, USA.
16
Vanderbilt University, Nashville, TN, USA.
17
University of Colorado Denver, Denver, CO, USA.
18
Baylor Research Institute, Plano, TX, USA.
19
Medstar Health, Washington, DC, USA.
20
Allegheny-Singer Research Institute, Pittsburgh, PA, USA.
21
Ohio State University, Columbus, OH, USA.
22
VU University Medical Center, Amsterdam, Netherlands.
23
Mayo Clinic Florida, Jacksonville, FL, USA.
24
Washington University, St Louis, MO, USA.
25
Golden Jubilee National Hospital, Glasgow, UK.
26
Royal Free Hospital, London, UK.
27
Royal Hallamshire Hospital, Sheffield, UK.
28
University of Newcastle, Newcastle, UK.
29
University of Pavia, Pavia, Italy.
30
University of Bordeaux, Bordeaux, France.
31
Intermountain Medical Center, Murray, UT, USA.
32
University of Cincinnati, Cincinnati OH, USA.
33
Duke University Medical Center, Durham, NC, USA; University of Kiel, Kiel, Germany.
34
University of Kiel, Kiel, Germany.
35
Mayo Clinic, Rochester, MN, USA.
36
Houston Methodist Research Institute, Houston, TX, USA.
37
Department of Medicine, University of Arizona, Tucson, AZ, USA.
38
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
39
National Heart and Lung Institute, Imperial College London, London, UK.
40
CAGE, Cincinnati, OH, USA.
41
Tufts-New England Medical Center, Boston, MA, USA.
42
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; University of Cincinnati, Cincinnati OH, USA.
43
Health Sciences Center, University of Colorado, Aurora, CO, USA.
44
Rhode Island Hospital, Providence, RI, USA.
45
Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
46
Indiana University, Indianapolis, IN, USA.
47
University of Lincoln, Lincoln, UK.
48
Royal United Hospitals Bath NHS Foundation Trust, Bath, UK.
49
Biomedical Informatics, Cincinnati, OH, USA.
50
Great Ormond Street Hospital, London, UK.
51
Inova Heart and Vascular Institute, Falls Church, VA, USA.
52
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.
53
Harbor-UCLA Medical Center, Torrance, CA, USA.
54
Department of Haematology, University of Cambridge, Cambridge, UK.
55
Papworth Hospital, Papworth, UK.
56
East Carolina University, Greenville, NC, USA.
57
Vanderbilt University School of Medicine, Nashville, TN, USA.
58
Columbia University, New York, NY, USA.
59
Wayne State University, Detroit, MI, USA.
60
University Hospital of Cleveland, Cleveland, OH, USA.
61
Boston University School of Medicine, Boston, MA, USA.
62
University of Pittsburgh, Pittsburgh, PA, USA.
63
Ambry Genetics, Aliso Viejo, CA, USA.
64
University of Minnesota, Minneapolis, MN, USA.
65
University of Texas Southwestern Medical Center, Dallas, TX, USA.
66
Louisiana State University Health, Shreveport, LA, USA.
67
University of Rochester Medical Center, Rochester, NY, USA.
68
Spectrum Health Hospitals, Grand Rapids, MI, USA.
69
Seattle Children's Hospital, Seattle, WA, USA.
70
University of Sheffield, Sheffield, UK.
71
City of Hope, Duarte, CA, USA.
72
Indiana University, Indianapolis, IN, USA. Electronic address: ankdesai@iu.edu.
73
Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address: nwm23@cam.ac.uk.
74
Department of Medicine, Imperial College London, London, UK. Electronic address: m.wilkins@imperial.ac.uk.

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.

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