Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.
Female
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Genotyping Techniques
/ methods
HLA-DP alpha-Chains
/ genetics
HLA-DP beta-Chains
/ genetics
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Pulmonary Arterial Hypertension
/ diagnosis
Risk Assessment
SOXF Transcription Factors
/ genetics
Signal Transduction
/ genetics
Survival Analysis
Journal
The Lancet. Respiratory medicine
ISSN: 2213-2619
Titre abrégé: Lancet Respir Med
Pays: England
ID NLM: 101605555
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
18
07
2018
revised:
20
09
2018
accepted:
26
09
2018
pubmed:
12
12
2018
medline:
16
4
2020
entrez:
12
12
2018
Statut:
ppublish
Résumé
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. 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. A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10 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. 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.
Sections du résumé
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
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.
Identifiants
pubmed: 30527956
pii: S2213-2600(18)30409-0
doi: 10.1016/S2213-2600(18)30409-0
pmc: PMC6391516
mid: NIHMS1008781
pii:
doi:
Substances chimiques
HLA-DP alpha-Chains
0
HLA-DP beta-Chains
0
HLA-DPA1 antigen
0
HLA-DPB1 antigen
0
SOX17 protein, human
0
SOXF Transcription Factors
0
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
227-238Subventions
Organisme : Medical Research Council
ID : MR/K020919/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/18/52/33808
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/15/59/31839
Pays : United Kingdom
Organisme : NCRR NIH HHS
ID : S10 RR025141
Pays : United States
Organisme : British Heart Foundation
ID : PG/11/116/29288
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/J011711/1
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : RC2 GM092618
Pays : United States
Organisme : Medical Research Council
ID : MR/L02036X/1
Pays : United Kingdom
Organisme : NCATS NIH HHS
ID : UL1 TR002243
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL136603
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141387
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000445
Pays : United States
Organisme : NHLBI NIH HHS
ID : R24 HL105333
Pays : United States
Organisme : Medical Research Council
ID : MC_UP_1102/20
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : U01 HG008666
Pays : United States
Organisme : British Heart Foundation
ID : SP/12/12/29836
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/13/4/30107
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/13/48/30453
Pays : United Kingdom
Organisme : NCRR NIH HHS
ID : UL1 RR024975
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
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.
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