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

TY - JOUR

T1 - Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

AU - Rhodes, Christopher J

AU - Batai, Ken

AU - Bleda, Marta

AU - Haimel, Matthias

AU - Southgate, Laura

AU - Germain, Marine

AU - Pauciulo, Michael W

AU - Hadinnapola, Charaka

AU - Aman, Jurjan

AU - Girerd, Barbara

AU - Arora, Amit

AU - Knight, Jo

AU - Hanscombe, Ken B

AU - Karnes, Jason H

AU - Kaakinen, Marika

AU - Gall, Henning

AU - Ulrich, Anna

AU - Harbaum, Lars

AU - Cebola, Inês

AU - Ferrer, Jorge

AU - Lutz, Katie

AU - Swietlik, Emilia M

AU - Ahmad, Ferhaan

AU - Amouyel, Philippe

AU - Archer, Stephen L

AU - Argula, Rahul

AU - Austin, Eric D

AU - Badesch, David

AU - Bakshi, Sahil

AU - Barnett, Christopher

AU - Benza, Raymond

AU - Bhatt, Nitin

AU - Bogaard, Harm J

AU - Burger, Charles D

AU - Chakinala, Murali

AU - Church, Colin

AU - Coghlan, John G

AU - Condliffe, Robin

AU - Corris, Paul A

AU - Danesino, Cesare

AU - Debette, Stéphanie

AU - Elliott, C Gregory

AU - Elwing, Jean

AU - Eyries, Melanie

AU - Fortin, Terry

AU - Franke, Andre

AU - Frantz, Robert P

AU - Frost, Adaani

AU - Garcia, Joe G N

AU - Ghio, Stefano

AU - Ghofrani, Hossein-Ardeschir

AU - Gibbs, J Simon R

AU - Harley, John

AU - He, Hua

AU - Hill, Nicholas S

AU - Hirsch, Russel

AU - Houweling, Arjan C

AU - Howard, Luke S

AU - Ivy, Dunbar

AU - Kiely, David G

AU - Klinger, James

AU - Kovacs, Gabor

AU - Lahm, Tim

AU - Laudes, Matthias

AU - Machado, Rajiv D

AU - Ross, Robert V MacKenzie

AU - Marsolo, Keith

AU - Martin, Lisa J

AU - Moledina, Shahin

AU - Montani, David

AU - Nathan, Steven D

AU - Newnham, Michael

AU - Olschewski, Andrea

AU - Olschewski, Horst

AU - Oudiz, Ronald J

AU - Ouwehand, Willem H

AU - Peacock, Andrew J

AU - Pepke-Zaba, Joanna

AU - Rehman, Zia

AU - Robbins, Ivan

AU - Roden, Dan M

AU - Rosenzweig, Erika B

AU - Saydain, Ghulam

AU - Scelsi, Laura

AU - Schilz, Robert

AU - Seeger, Werner

AU - Shaffer, Christian M

AU - Simms, Robert W

AU - Simon, Marc

AU - Sitbon, Olivier

AU - Suntharalingam, Jay

AU - Tang, Haiyang

AU - Tchourbanov, Alexander Y

AU - Thenappan, Thenappan

AU - Torres, Fernando

AU - Toshner, Mark R

AU - Treacy, Carmen M

AU - Noordegraaf, Anton Vonk

AU - Waisfisz, Quinten

AU - Walsworth, Anna K

AU - Walter, Robert E

AU - Wharton, John

AU - White, R James

AU - Wilt, Jeffrey

AU - Wort, Stephen J

AU - Yung, Delphine

AU - Lawrie, Allan

AU - Humbert, Marc

AU - Soubrier, Florent

AU - Trégouët, David-Alexandre

AU - Prokopenko, Inga

AU - Kittles, Richard

AU - Gräf, Stefan

AU - Nichols, William C

AU - Trembath, Richard C

AU - Desai, Ankit A

AU - Morrell, Nicholas W

AU - Wilkins, Martin R

AU - NIHR BioResource

N1 - Copyright © 2018 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.

PY - 2019/3

Y1 - 2019/3

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/S2213-2600(18)30409-0

DO - 10.1016/S2213-2600(18)30409-0

M3 - SCORING: Journal article

C2 - 30527956

VL - 7

SP - 227

EP - 238

JO - LANCET RESP MED

JF - LANCET RESP MED

SN - 2213-2600

IS - 3

ER -