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

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Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis. / UK NIHR BioResource Rare Diseases Consortium; UK PAH Cohort Study Consortium; US PAH Biobank Consortium et al.
In: Lancet Respiratory Medicine, Vol. 7, No. 3, 01.03.2019, p. 227-238.

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Harvard

UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium, Rhodes, CJ, Batai, K, Bleda, M, Haimel, M, Southgate, L, Germain, M, Pauciulo, MW, Hadinnapola, C, Aman, J, Girerd, B, Arora, A, Knight, J, Hanscombe, KB, 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 2019, 'Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis', Lancet Respiratory Medicine, vol. 7, no. 3, pp. 227-238. https://doi.org/10.1016/S2213-2600(18)30409-0

APA

UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium, Rhodes, C. J., Batai, K., Bleda, M., Haimel, M., Southgate, L., Germain, M., Pauciulo, M. W., Hadinnapola, C., Aman, J., Girerd, B., Arora, A., Knight, J., Hanscombe, K. B., Karnes, J. H., Kaakinen, M., Gall, H., ... Ghio, S. (2019). Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis. Lancet Respiratory Medicine, 7(3), 227-238. https://doi.org/10.1016/S2213-2600(18)30409-0

Vancouver

UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium, Rhodes CJ, Batai K, Bleda M et al. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis. Lancet Respiratory Medicine. 2019 Mar 1;7(3):227-238. Epub 2018 Dec 5. doi: 10.1016/S2213-2600(18)30409-0

Author

UK NIHR BioResource Rare Diseases Consortium ; UK PAH Cohort Study Consortium ; US PAH Biobank Consortium et al. / Genetic determinants of risk in pulmonary arterial hypertension : international genome-wide association studies and meta-analysis. In: Lancet Respiratory Medicine. 2019 ; Vol. 7, No. 3. pp. 227-238.

Bibtex

@article{f27ef0a88c874850b25a61744779b1fe,
title = "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, Universit{\'e} Paris-Sud, and French ANR.",
author = "{UK NIHR BioResource Rare Diseases Consortium} and {UK PAH Cohort Study Consortium} and {US PAH Biobank Consortium} and Rhodes, {Christopher J} and Ken Batai and Marta Bleda and Matthias Haimel and Laura Southgate and Marine Germain and Pauciulo, {Michael W} and Charaka Hadinnapola and Jurjan Aman and Barbara Girerd and Amit Arora and Jo Knight and Hanscombe, {Ken B} and Karnes, {Jason H} and Marika Kaakinen and Henning Gall and Anna Ulrich and Lars Harbaum and In{\^e}s Cebola and Jorge Ferrer and Katie Lutz and Swietlik, {Emilia M} and Ferhaan Ahmad and Philippe Amouyel and Archer, {Stephen L} and Rahul Argula and Austin, {Eric D} and David Badesch and Sahil Bakshi and Christopher Barnett and Raymond Benza and Nitin Bhatt and Bogaard, {Harm J} and Burger, {Charles D} and Murali Chakinala and Colin Church and Coghlan, {John G} and Robin Condliffe and Corris, {Paul A} and Cesare Danesino and St{\'e}phanie Debette and Elliott, {C Gregory} and Jean Elwing and Melanie Eyries and Terry Fortin and Andre Franke and Frantz, {Robert P} and Adaani Frost and Garcia, {Joe G N} and Stefano Ghio",
note = "Copyright {\textcopyright} 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.",
year = "2019",
month = mar,
day = "1",
doi = "10.1016/S2213-2600(18)30409-0",
language = "English",
volume = "7",
pages = "227--238",
journal = "Lancet Respiratory Medicine",
issn = "2213-2600",
publisher = "Elsevier Limited",
number = "3",

}

RIS

TY - JOUR

T1 - Genetic determinants of risk in pulmonary arterial hypertension

T2 - international genome-wide association studies and meta-analysis

AU - UK NIHR BioResource Rare Diseases Consortium

AU - UK PAH Cohort Study Consortium

AU - US PAH Biobank Consortium

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

N1 - 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.

PY - 2019/3/1

Y1 - 2019/3/1

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.

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

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

M3 - Journal article

C2 - 30527956

VL - 7

SP - 227

EP - 238

JO - Lancet Respiratory Medicine

JF - Lancet Respiratory Medicine

SN - 2213-2600

IS - 3

ER -