Meta-Analysis

. 2019 Mar;7(3):227-238.

doi: 10.1016/S2213-2600(18)30409-0. Epub 2018 Dec 5.

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

Christopher J Rhodes¹, Ken Batai², Marta Bleda³, Matthias Haimel³, Laura Southgate⁴, Marine Germain⁵, Michael W Pauciulo⁶, Charaka Hadinnapola³, Jurjan Aman¹, Barbara Girerd⁷, Amit Arora², Jo Knight⁸, Ken B Hanscombe⁹, Jason H Karnes¹⁰, Marika Kaakinen¹, Henning Gall¹¹, Anna Ulrich¹, Lars Harbaum¹, Inês Cebola¹, Jorge Ferrer¹, Katie Lutz⁶, Emilia M Swietlik³, Ferhaan Ahmad¹², Philippe Amouyel¹³, Stephen L Archer¹⁴, Rahul Argula¹⁵, Eric D Austin¹⁶, David Badesch¹⁷, Sahil Bakshi¹⁸, Christopher Barnett¹⁹, Raymond Benza²⁰, Nitin Bhatt²¹, Harm J Bogaard²², Charles D Burger²³, Murali Chakinala²⁴, Colin Church²⁵, John G Coghlan²⁶, Robin Condliffe²⁷, Paul A Corris²⁸, Cesare Danesino²⁹, Stéphanie Debette³⁰, C Gregory Elliott³¹, Jean Elwing³², Melanie Eyries⁵, Terry Fortin³³, Andre Franke³⁴, Robert P Frantz³⁵, Adaani Frost³⁶, Joe G N Garcia³⁷, Stefano Ghio³⁸, Hossein-Ardeschir Ghofrani¹¹, J Simon R Gibbs³⁹, John Harley⁴⁰, Hua He⁶, Nicholas S Hill⁴¹, Russel Hirsch⁴², Arjan C Houweling²², Luke S Howard³⁹, Dunbar Ivy⁴³, David G Kiely²⁷, James Klinger⁴⁴, Gabor Kovacs⁴⁵, Tim Lahm⁴⁶, Matthias Laudes³⁴, Rajiv D Machado⁴⁷, Robert V MacKenzie Ross⁴⁸, Keith Marsolo⁴⁹, Lisa J Martin⁶, Shahin Moledina⁵⁰, David Montani⁷, Steven D Nathan⁵¹, Michael Newnham⁵², Andrea Olschewski⁴⁵, Horst Olschewski⁴⁵, Ronald J Oudiz⁵³, Willem H Ouwehand⁵⁴, Andrew J Peacock²⁵, Joanna Pepke-Zaba⁵⁵, Zia Rehman⁵⁶, Ivan Robbins⁵⁷, Dan M Roden⁵⁷, Erika B Rosenzweig⁵⁸, Ghulam Saydain⁵⁹, Laura Scelsi³⁸, Robert Schilz⁶⁰, Werner Seeger¹¹, Christian M Shaffer⁵⁷, Robert W Simms⁶¹, Marc Simon⁶², Olivier Sitbon⁷, Jay Suntharalingam⁴⁸, Haiyang Tang³⁷, Alexander Y Tchourbanov⁶³, Thenappan Thenappan⁶⁴, Fernando Torres⁶⁵, Mark R Toshner³, Carmen M Treacy³, Anton Vonk Noordegraaf²², Quinten Waisfisz²², Anna K Walsworth⁶, Robert E Walter⁶⁶, John Wharton¹, R James White⁶⁷, Jeffrey Wilt⁶⁸, Stephen J Wort³⁹, Delphine Yung⁶⁹, Allan Lawrie⁷⁰, Marc Humbert⁷, Florent Soubrier⁵, David-Alexandre Trégouët⁵, Inga Prokopenko¹, Richard Kittles⁷¹, Stefan Gräf³, William C Nichols⁶, Richard C Trembath⁹, Ankit A Desai⁷², Nicholas W Morrell⁷³, Martin R Wilkins⁷⁴; UK NIHR BioResource Rare Diseases Consortium; UK PAH Cohort Study Consortium; US PAH Biobank Consortium

Affiliations

¹ Department of Medicine, Imperial College London, London, UK.
² Department of Surgery, University of Arizona, Tucson, AZ, USA.
³ Department of Medicine, University of Cambridge, Cambridge, UK.
⁴ Molecular and Clinical Sciences Research Institute, St George's University of London, London, UK.
⁵ Sorbonne Universités, UPMC, INSERM, Paris, France.
⁶ Human Genetics, Cincinnati, OH, USA.
⁷ University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France.
⁸ Data Science Institute, Lancaster University, Lancaster, UK.
⁹ Genetics and Molecular Medicine, King's College London, London, UK.
¹⁰ Pharmacy Practice and Science, University of Arizona, Tucson, AZ, USA.
¹¹ University of Giessen and Marburg Lung Center, Giessen, Germany.
¹² University of Iowa, Iowa City, IA, USA.
¹³ University of Lille, Lille, France.
¹⁴ Queen's University, Kingston, ON, Canada.
¹⁵ Medical University of South Carolina, Charleston, SC, USA.
¹⁶ Vanderbilt University, Nashville, TN, USA.
¹⁷ University of Colorado Denver, Denver, CO, USA.
¹⁸ Baylor Research Institute, Plano, TX, USA.
¹⁹ Medstar Health, Washington, DC, USA.
²⁰ Allegheny-Singer Research Institute, Pittsburgh, PA, USA.
²¹ Ohio State University, Columbus, OH, USA.
²² VU University Medical Center, Amsterdam, Netherlands.
²³ Mayo Clinic Florida, Jacksonville, FL, USA.
²⁴ Washington University, St Louis, MO, USA.
²⁵ Golden Jubilee National Hospital, Glasgow, UK.
²⁶ Royal Free Hospital, London, UK.
²⁷ Royal Hallamshire Hospital, Sheffield, UK.
²⁸ University of Newcastle, Newcastle, UK.
²⁹ University of Pavia, Pavia, Italy.
³⁰ University of Bordeaux, Bordeaux, France.
³¹ Intermountain Medical Center, Murray, UT, USA.
³² University of Cincinnati, Cincinnati OH, USA.
³³ Duke University Medical Center, Durham, NC, USA; University of Kiel, Kiel, Germany.
³⁴ University of Kiel, Kiel, Germany.
³⁵ Mayo Clinic, Rochester, MN, USA.
³⁶ Houston Methodist Research Institute, Houston, TX, USA.
³⁷ Department of Medicine, University of Arizona, Tucson, AZ, USA.
³⁸ Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
³⁹ National Heart and Lung Institute, Imperial College London, London, UK.
⁴⁰ CAGE, Cincinnati, OH, USA.
⁴¹ Tufts-New England Medical Center, Boston, MA, USA.
⁴² Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; University of Cincinnati, Cincinnati OH, USA.
⁴³ Health Sciences Center, University of Colorado, Aurora, CO, USA.
⁴⁴ Rhode Island Hospital, Providence, RI, USA.
⁴⁵ Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
⁴⁶ Indiana University, Indianapolis, IN, USA.
⁴⁷ University of Lincoln, Lincoln, UK.
⁴⁸ Royal United Hospitals Bath NHS Foundation Trust, Bath, UK.
⁴⁹ Biomedical Informatics, Cincinnati, OH, USA.
⁵⁰ Great Ormond Street Hospital, London, UK.
⁵¹ Inova Heart and Vascular Institute, Falls Church, VA, USA.
⁵² Department of Medicine, University of Cambridge, Cambridge, UK; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
⁵³ Harbor-UCLA Medical Center, Torrance, CA, USA.
⁵⁴ Department of Haematology, University of Cambridge, Cambridge, UK.
⁵⁵ Papworth Hospital, Papworth, UK.
⁵⁶ East Carolina University, Greenville, NC, USA.
⁵⁷ Vanderbilt University School of Medicine, Nashville, TN, USA.
⁵⁸ Columbia University, New York, NY, USA.
⁵⁹ Wayne State University, Detroit, MI, USA.
⁶⁰ University Hospital of Cleveland, Cleveland, OH, USA.
⁶¹ Boston University School of Medicine, Boston, MA, USA.
⁶² University of Pittsburgh, Pittsburgh, PA, USA.
⁶³ Ambry Genetics, Aliso Viejo, CA, USA.
⁶⁴ University of Minnesota, Minneapolis, MN, USA.
⁶⁵ University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶⁶ Louisiana State University Health, Shreveport, LA, USA.
⁶⁷ University of Rochester Medical Center, Rochester, NY, USA.
⁶⁸ Spectrum Health Hospitals, Grand Rapids, MI, USA.
⁶⁹ Seattle Children's Hospital, Seattle, WA, USA.
⁷⁰ University of Sheffield, Sheffield, UK.
⁷¹ City of Hope, Duarte, CA, USA.
⁷² Indiana University, Indianapolis, IN, USA. Electronic address: ankdesai@iu.edu.
⁷³ Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address: nwm23@cam.ac.uk.
⁷⁴ Department of Medicine, Imperial College London, London, UK. Electronic address: m.wilkins@imperial.ac.uk.

PMID: 30527956
PMCID: PMC6391516
DOI: 10.1016/S2213-2600(18)30409-0

Meta-Analysis

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

Christopher J Rhodes et al. Lancet Respir Med. 2019 Mar.

. 2019 Mar;7(3):227-238.

doi: 10.1016/S2213-2600(18)30409-0. Epub 2018 Dec 5.

Authors

Affiliations

¹ Department of Medicine, Imperial College London, London, UK.
² Department of Surgery, University of Arizona, Tucson, AZ, USA.
³ Department of Medicine, University of Cambridge, Cambridge, UK.
⁴ Molecular and Clinical Sciences Research Institute, St George's University of London, London, UK.
⁵ Sorbonne Universités, UPMC, INSERM, Paris, France.
⁶ Human Genetics, Cincinnati, OH, USA.
⁷ University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France.
⁸ Data Science Institute, Lancaster University, Lancaster, UK.
⁹ Genetics and Molecular Medicine, King's College London, London, UK.
¹⁰ Pharmacy Practice and Science, University of Arizona, Tucson, AZ, USA.
¹¹ University of Giessen and Marburg Lung Center, Giessen, Germany.
¹² University of Iowa, Iowa City, IA, USA.
¹³ University of Lille, Lille, France.
¹⁴ Queen's University, Kingston, ON, Canada.
¹⁵ Medical University of South Carolina, Charleston, SC, USA.
¹⁶ Vanderbilt University, Nashville, TN, USA.
¹⁷ University of Colorado Denver, Denver, CO, USA.
¹⁸ Baylor Research Institute, Plano, TX, USA.
¹⁹ Medstar Health, Washington, DC, USA.
²⁰ Allegheny-Singer Research Institute, Pittsburgh, PA, USA.
²¹ Ohio State University, Columbus, OH, USA.
²² VU University Medical Center, Amsterdam, Netherlands.
²³ Mayo Clinic Florida, Jacksonville, FL, USA.
²⁴ Washington University, St Louis, MO, USA.
²⁵ Golden Jubilee National Hospital, Glasgow, UK.
²⁶ Royal Free Hospital, London, UK.
²⁷ Royal Hallamshire Hospital, Sheffield, UK.
²⁸ University of Newcastle, Newcastle, UK.
²⁹ University of Pavia, Pavia, Italy.
³⁰ University of Bordeaux, Bordeaux, France.
³¹ Intermountain Medical Center, Murray, UT, USA.
³² University of Cincinnati, Cincinnati OH, USA.
³³ Duke University Medical Center, Durham, NC, USA; University of Kiel, Kiel, Germany.
³⁴ University of Kiel, Kiel, Germany.
³⁵ Mayo Clinic, Rochester, MN, USA.
³⁶ Houston Methodist Research Institute, Houston, TX, USA.
³⁷ Department of Medicine, University of Arizona, Tucson, AZ, USA.
³⁸ Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
³⁹ National Heart and Lung Institute, Imperial College London, London, UK.
⁴⁰ CAGE, Cincinnati, OH, USA.
⁴¹ Tufts-New England Medical Center, Boston, MA, USA.
⁴² Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; University of Cincinnati, Cincinnati OH, USA.
⁴³ Health Sciences Center, University of Colorado, Aurora, CO, USA.
⁴⁴ Rhode Island Hospital, Providence, RI, USA.
⁴⁵ Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
⁴⁶ Indiana University, Indianapolis, IN, USA.
⁴⁷ University of Lincoln, Lincoln, UK.
⁴⁸ Royal United Hospitals Bath NHS Foundation Trust, Bath, UK.
⁴⁹ Biomedical Informatics, Cincinnati, OH, USA.
⁵⁰ Great Ormond Street Hospital, London, UK.
⁵¹ Inova Heart and Vascular Institute, Falls Church, VA, USA.
⁵² Department of Medicine, University of Cambridge, Cambridge, UK; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
⁵³ Harbor-UCLA Medical Center, Torrance, CA, USA.
⁵⁴ Department of Haematology, University of Cambridge, Cambridge, UK.
⁵⁵ Papworth Hospital, Papworth, UK.
⁵⁶ East Carolina University, Greenville, NC, USA.
⁵⁷ Vanderbilt University School of Medicine, Nashville, TN, USA.
⁵⁸ Columbia University, New York, NY, USA.
⁵⁹ Wayne State University, Detroit, MI, USA.
⁶⁰ University Hospital of Cleveland, Cleveland, OH, USA.
⁶¹ Boston University School of Medicine, Boston, MA, USA.
⁶² University of Pittsburgh, Pittsburgh, PA, USA.
⁶³ Ambry Genetics, Aliso Viejo, CA, USA.
⁶⁴ University of Minnesota, Minneapolis, MN, USA.
⁶⁵ University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶⁶ Louisiana State University Health, Shreveport, LA, USA.
⁶⁷ University of Rochester Medical Center, Rochester, NY, USA.
⁶⁸ Spectrum Health Hospitals, Grand Rapids, MI, USA.
⁶⁹ Seattle Children's Hospital, Seattle, WA, USA.
⁷⁰ University of Sheffield, Sheffield, UK.
⁷¹ City of Hope, Duarte, CA, USA.
⁷² Indiana University, Indianapolis, IN, USA. Electronic address: ankdesai@iu.edu.
⁷³ Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address: nwm23@cam.ac.uk.
⁷⁴ Department of Medicine, Imperial College London, London, UK. Electronic address: m.wilkins@imperial.ac.uk.

PMID: 30527956
PMCID: PMC6391516
DOI: 10.1016/S2213-2600(18)30409-0

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.

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Figures

**Figure 1**
Study design *HLA-DPA1* and *HLA-DPB1* are collectively referred to as *HLA-DPA1/DPB1* in this Article. BHFPAH=British Heart Foundation Pulmonary Arterial Hypertension study. GWAS=genome-wide association study. NIHRBR=National Institute for Health Research BioResource study. PAH=pulmonary arterial hypertension. PAHB=PAH Biobank study. PHAAR=Pulmonary Hypertension Allele-Associated Risk study.

**Figure 2**
A meta-analysis of all cohorts and regional plots of novel loci The regional plots indicate variant location at the *HLA-DPA1* and *HLA-DPB1* (collectively referred to as *HLA-DPA1/DPB1* in this Article) locus and linkage disequilibrium structure at *SOX17* locus. At the *SOX17* locus, several variants associated with pulmonary arterial hypertension are in very weak or no linkage disequilibrium (r<0·2) with the lead single-nucleotide polymorphism (SNP), rs10103692. We refer to these variants as *SOX17* signal 1 and the most significant variant, rs13266183, is indicated. The variants coloured as in linkage disequilibrium with rs10103692 comprise signal 2.

**Figure 3**
In-silico analysis of *SOX17* locus Hi-C data from human umbilical vein endothelial cells (hUVECs) indicate regions of DNA found in close proximity in the three-dimensional structure. The genomic region containing the significant variants identified by the genome-wide association study (GWAS) analysis is indicated by a black box, overlapping a topologically associated domain (TAD) indicated in blue, which contains only *SOX17.* Mapping of *SOX17* locus variants associated with pulmonary arterial hypertension with public epigenomic data is underneath Hi-C data. The credible set indicates positions of variants 99% likely to contain the causal variants. Auxiliary hidden Markov models, which summarise epigenomic data to predict the functional status of genomic regions in different tissues or cells, are shown. Epigenomic data in endothelial cells including hUVECs, human pulmonary artery endothelial cells (hPAECs), and endothelial progenitor cells (EPCs), indicate areas likely to contain active regulatory regions and promoters. Markers include histone H3 lysine 4 monomethylation (H3K4Me1; often found in enhancers) and trimethylation (H3K4Me3; strongly observed in promoters) and H3 lysine 27 acetylation (H3K27Ac; often found in active regulatory regions). The blue vertical blocks indicate where epigenomic data suggest a putative enhancer region, some overlapped by variants associated with pulmonary arterial hypertension. These regions were cloned for the luciferase reporter experiments (figure 4B). DHSs=DNase I hypersenstivity sites.

**Figure 4**
In-vitro analysis of *SOX17* locus (A) Process for haplotype-specific reporter construct derivation. 100 bp genomic DNA inserts containing *SOX17* single-nucleotide polymorphisms (SNPs) are isolated from endothelial progenitor cells derived from a patient with pulmonary arterial hypertension (PAH) heterozygous for the *SOX17* SNPs. Colonies of transformed bacteria can be sequenced to determine alleles present in the product. Transfection of luciferase reporter constructs containing inserts into human pulmonary artery endothelial cells (hPAECs) allows for determination of luciferase activity. (B) Luciferase reporter assay results. Luciferase:Renilla ratios relative to the empty vector demonstrate haplotype-dependent enhancement of promoter activity. Enhancer effects were tested by one-way analysis of variance followed by Dunnett's post-hoc tests: rs10958403-G/A and rs765727-C/T were both p<0·0001 significant versus empty vector; variant effects of these two SNPs were tested by t test. The mean (SEM; error bars) of five experiments is shown. (C) Relative expression of *SOX17:ACTB* in hPAECs on CRISPR-mediated repression of the near *SOX17* genome-wide association study (GWAS) locus. The mean (SEM; error bars) of four measurements in a representative experiment is shown. Three further experiments showed consistent results. Blue fluorescent protein (BFP), enhanced green fluorescent protein (eGFP), and control, which refers to a region between the enhancer region and the *SOX17* gene that is negative for regulatory markers, are used as negative controls. The *SOX17* promoter was targeted as a positive control of repression. Significance shown versus BFP by Dunnett's post-hoc analysis. (D) Relative expression of *MRPL15:ACTB* in hPAECs on CRISPR-mediated repression of the GWAS locus.

**Figure 5**
Clinical impact of *HLA-DPB1* rs2856830 (A) Age at diagnosis by genotype in four cohorts of patients with pulmonary arterial hypertension (PAH). Bars indicate medians (IQRs); numbers given are median values in subgroups. The p value shown is from a linear regression model correcting for cohort differences. (B) Forest plot showing hazard ratios for the rs2856830 6:33041734 T/T versus C/C genotypes, corrected for age and sex in Cox regression survival analyses in each cohort, individually and with meta-analysis results. Error bars indicate 95% CIs. (C) Kaplan-Meier survival plot in patients with pulmonary arterial hypertension divided into groups on the basis of the genotype of *HLA-DPA1* and *HLA-DPB1* single-nucleotide polymorphism (SNP) rs2856830 in all cohorts. Numbers at risk indicates numbers at risk in each time period, which increases as truncated patients are recruited into the study after diagnosis and decreases as patient follow-up ends. Significance from the log rank test is given. BHFPAH=British Heart Foundation Pulmonary Arterial Hypertension study. NIHRBR=National Institute for Health Research BioResource study. PAHB=PAH Biobank study. PHAAR=Pulmonary Hypertension Allele-Associated Risk study.

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Research Materials