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.

• Authors: Christopher J Rhodes, Ken Batai, Marta Bleda, Matthias Haimel, Laura Southgate, Marine Germain, Michael W Pauciulo, Charaka Hadinnapola, Jurjan Aman, Barbara Girerd, Amit Arora, Jo Knight, Ken B Hanscombe, Jason H Karnes, Marika Kaakinen, Henning Gall, Anna Ulrich, Lars Harbaum, Inês Cebola, Jorge Ferrer, Katie Lutz, Emilia M Swietlik, Ferhaan Ahmad, Philippe Amouyel, Stephen L Archer, Rahul Argula, Eric D Austin, David Badesch, Sahil Bakshi, Christopher Barnett, Raymond Benza, Nitin Bhatt, Harm J Bogaard, Charles D Burger, Murali Chakinala, Colin Church, John G Coghlan, Robin Condliffe, Paul A Corris, Cesare Danesino, Stéphanie Debette, C Gregory Elliott, Jean Elwing, Melanie Eyries, Terry Fortin, Andre Franke, Robert P Frantz, Adaani Frost, Joe G N Garcia, Stefano Ghio, Hossein-Ardeschir Ghofrani, J Simon R Gibbs, John Harley, Hua He, Nicholas S Hill, Russel Hirsch, Arjan C Houweling, Luke S Howard, Dunbar Ivy, David G Kiely, James Klinger, Gabor Kovacs, Tim Lahm, Matthias Laudes, Rajiv D Machado, Robert V MacKenzie Ross, Keith Marsolo, Lisa J Martin, Shahin Moledina, David Montani, Steven D Nathan, Michael Newnham, Andrea Olschewski, Horst Olschewski, Ronald J Oudiz, Willem H Ouwehand, Andrew J Peacock, Joanna Pepke-Zaba, Zia Rehman, Ivan Robbins, Dan M Roden, Erika B Rosenzweig, Ghulam Saydain, Laura Scelsi, Robert Schilz, Werner Seeger, Christian M Shaffer, Robert W Simms, Marc Simon, Olivier Sitbon, Jay Suntharalingam, Haiyang Tang, Alexander Y Tchourbanov, Thenappan Thenappan, Fernando Torres, Mark R Toshner, Carmen M Treacy, Anton Vonk Noordegraaf, Quinten Waisfisz, Anna K Walsworth, Robert E Walter, John Wharton, R James White, Jeffrey Wilt, Stephen J Wort, Delphine Yung, Allan Lawrie, Marc Humbert, Florent Soubrier, David-Alexandre Trégouët, Inga Prokopenko, Richard Kittles, Stefan Gräf, William C Nichols, Richard C Trembath, Ankit A Desai, Nicholas W Morrell, Martin R Wilkins, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium
• Journal: The Lancet. Respiratory medicine (Lancet Respir Med) Vol. 7 Issue 3 Pg. 227-238 (03 2019) ISSN: 2213-2619 [Electronic] England
• PMID: 30527956 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• 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.

Chemical References

• HLA-DP alpha-Chains
• HLA-DP beta-Chains
• HLA-DPA1 antigen
• HLA-DPB1 antigen
• SOX17 protein, human
• SOXF Transcription Factors

Topics

• 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, genetics, metabolism, mortality)
• Risk Assessment
• SOXF Transcription Factors (genetics)
• Signal Transduction (genetics)
• Survival Analysis