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


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.

SUBMITTER: Rhodes CJ 

PROVIDER: S-EPMC6391516 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Rhodes Christopher J CJ   Batai Ken K   Bleda Marta M   Haimel Matthias M   Southgate Laura L   Germain Marine M   Pauciulo Michael W MW   Hadinnapola Charaka C   Aman Jurjan J   Girerd Barbara B   Arora Amit A   Knight Jo J   Hanscombe Ken B KB   Karnes Jason H JH   Kaakinen Marika M   Gall Henning H   Ulrich Anna A   Harbaum Lars L   Cebola Inês I   Ferrer Jorge J   Lutz Katie K   Swietlik Emilia M EM   Ahmad Ferhaan F   Amouyel Philippe P   Archer Stephen L SL   Argula Rahul R   Austin Eric D ED   Badesch David D   Bakshi Sahil S   Barnett Christopher C   Benza Raymond R   Bhatt Nitin N   Bogaard Harm J HJ   Burger Charles D CD   Chakinala Murali M   Church Colin C   Coghlan John G JG   Condliffe Robin R   Corris Paul A PA   Danesino Cesare C   Debette Stéphanie S   Elliott C Gregory CG   Elwing Jean J   Eyries Melanie M   Fortin Terry T   Franke Andre A   Frantz Robert P RP   Frost Adaani A   Garcia Joe G N JGN   Ghio Stefano S   Ghofrani Hossein-Ardeschir HA   Gibbs J Simon R JSR   Harley John J   He Hua H   Hill Nicholas S NS   Hirsch Russel R   Houweling Arjan C AC   Howard Luke S LS   Ivy Dunbar D   Kiely David G DG   Klinger James J   Kovacs Gabor G   Lahm Tim T   Laudes Matthias M   Machado Rajiv D RD   MacKenzie Ross Robert V RV   Marsolo Keith K   Martin Lisa J LJ   Moledina Shahin S   Montani David D   Nathan Steven D SD   Newnham Michael M   Olschewski Andrea A   Olschewski Horst H   Oudiz Ronald J RJ   Ouwehand Willem H WH   Peacock Andrew J AJ   Pepke-Zaba Joanna J   Rehman Zia Z   Robbins Ivan I   Roden Dan M DM   Rosenzweig Erika B EB   Saydain Ghulam G   Scelsi Laura L   Schilz Robert R   Seeger Werner W   Shaffer Christian M CM   Simms Robert W RW   Simon Marc M   Sitbon Olivier O   Suntharalingam Jay J   Tang Haiyang H   Tchourbanov Alexander Y AY   Thenappan Thenappan T   Torres Fernando F   Toshner Mark R MR   Treacy Carmen M CM   Vonk Noordegraaf Anton A   Waisfisz Quinten Q   Walsworth Anna K AK   Walter Robert E RE   Wharton John J   White R James RJ   Wilt Jeffrey J   Wort Stephen J SJ   Yung Delphine D   Lawrie Allan A   Humbert Marc M   Soubrier Florent F   Trégouët David-Alexandre DA   Prokopenko Inga I   Kittles Richard R   Gräf Stefan S   Nichols William C WC   Trembath Richard C RC   Desai Ankit A AA   Morrell Nicholas W NW   Wilkins Martin R MR  

The Lancet. Respiratory medicine 20181205 3


<h4>Background</h4>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.<h4>Methods</h4>We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS  ...[more]

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