Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis

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Title: Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis
Authors: Rhodes, CJ
Batai, K
Bleda, M
Haimel, M
Southgate, L
Germain, M
Pauciulo, MW
Hadinnapola, C
Aman, J
Girerd, B
Arora, A
Robbins, I
Roden, DM
Rosenzweig, EB
Saydain, G
Scelsi, L
Schilz, R
Seeger, W
Shaffer, CM
Simms, RW
Simon, M
Walter, RE
Sitbon, O
Suntharalingam, J
Tang, H
Tchourbanov, AY
Thenappan, T
Torres, F
Toshner, MR
Treacy, CM
Noordegraaf, AV
Waisfisz, Q
Wharton, J
Walsworth, AK
White, RJ
Wilt, J
Wort, SJ
Yung, D
Lawrie, A
Humbert, M
Soubrier, F
Trégouët, D-A
Knight, J
Prokopenko, I
Kittles, R
Gräf, S
Nichols, WC
Trembath, RC
Desai, AA
Morrell, NW
Wilkins, MR
UK NIHR BioResource Rare Diseases Consortium
UK PAH Cohort Study Consortium
Hanscombe, KB
US PAH Biobank Consortium
Karnes, JH
Kaakinen, M
Gall, H
Ulrich, A
Harbaum, L
Cebola, I
Ferrer, J
Lutz, K
Swietlik, EM
Ahmad, F
Amouyel, P
Archer, SL
Argula, R
Austin, ED
Badesch, D
Bakshi, S
Barnett, C
Benza, R
Bhatt, N
Bogaard, HJ
Burger, CD
Chakinala, M
Church, C
Coghlan, JG
Condliffe, R
Corris, PA
Danesino, C
Debette, S
Elliott, CG
Elwing, J
Eyries, M
Fortin, T
Franke, A
Frantz, RP
Frost, A
Garcia, JGN
Ghio, S
Ghofrani, H-A
Gibbs, JSR
Harley, J
He, H
Hill, NS
Hirsch, R
Houweling, AC
Howard, LS
Ivy, D
Kiely, DG
Klinger, J
Kovacs, G
Lahm, T
Laudes, M
Machado, RD
Ross, RVM
Marsolo, K
Martin, LJ
Moledina, S
Montani, D
Nathan, SD
Newnham, M
Olschewski, A
Olschewski, H
Oudiz, RJ
Ouwehand, WH
Peacock, AJ
Pepke-Zaba, J
Rehman, Z
Item Type: Journal Article
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.
Issue Date: 1-Mar-2019
Date of Acceptance: 26-Sep-2018
ISSN: 2213-2600
Publisher: Elsevier
Start Page: 227
End Page: 238
Journal / Book Title: Lancet Respiratory Medicine
Volume: 7
Issue: 3
Copyright Statement: © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license .
Sponsor/Funder: British Heart Foundation
Wellcome Trust
Medical Research Council (MRC)
Funder's Grant Number: FS/15/59/31839
Keywords: Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
Respiratory System
General & Internal Medicine
UK NIHR BioResource Rare Diseases Consortium
UK PAH Cohort Study Consortium
US PAH Biobank Consortium
Publication Status: Published
Online Publication Date: 2018-12-05
Appears in Collections:National Heart and Lung Institute
Department of Medicine
Faculty of Medicine

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