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

dc.rights.licenseopenen_US
dc.contributor.authorRHODES, C. J.
dc.contributor.authorBATAI, K.
dc.contributor.authorBLEDA, M.
dc.contributor.authorHAIMEL, M.
dc.contributor.authorSOUTHGATE, L.
dc.contributor.authorGERMAIN, M.
dc.contributor.authorPAUCIULO, M. W.
dc.contributor.authorHADINNAPOLA, C.
dc.contributor.authorAMAN, J.
dc.contributor.authorGIRERD, B.
dc.contributor.authorARORA, A.
dc.contributor.authorKNIGHT, J.
dc.contributor.authorHANSCOMBE, K. B.
dc.contributor.authorKARNES, J. H.
dc.contributor.authorKAAKINEN, M.
dc.contributor.authorGALL, H.
dc.contributor.authorULRICH, A.
dc.contributor.authorHARBAUM, L.
dc.contributor.authorCEBOLA, I.
dc.contributor.authorFERRER, J.
dc.contributor.authorLUTZ, K.
dc.contributor.authorSWIETLIK, E. M.
dc.contributor.authorAHMAD, F.
dc.contributor.authorAMOUYEL, Philippe
dc.contributor.authorARCHER, S. L.
dc.contributor.authorARGULA, R.
dc.contributor.authorAUSTIN, E. D.
dc.contributor.authorBADESCH, D.
dc.contributor.authorBAKSHI, S.
dc.contributor.authorBARNETT, C.
dc.contributor.authorBENZA, R.
dc.contributor.authorBHATT, N.
dc.contributor.authorBOGAARD, H. J.
dc.contributor.authorBURGER, C. D.
dc.contributor.authorCHAKINALA, M.
dc.contributor.authorCHURCH, C.
dc.contributor.authorCOGHLAN, J. G.
dc.contributor.authorCONDLIFFE, R.
dc.contributor.authorCORRIS, P. A.
dc.contributor.authorDANESINO, C.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDEBETTE, Stephanie
dc.contributor.authorELLIOTT, C. G.
dc.contributor.authorELWING, J.
dc.contributor.authorEYRIES, M.
dc.contributor.authorFORTIN, T.
dc.contributor.authorFRANKE, A.
dc.contributor.authorFRANTZ, R. P.
dc.contributor.authorFROST, A.
dc.contributor.authorGARCIA, J. G. N.
dc.contributor.authorGHIO, S.
dc.contributor.authorGHOFRANI, H. A.
dc.contributor.authorGIBBS, J. S. R.
dc.contributor.authorHARLEY, J.
dc.contributor.authorHE, H.
dc.contributor.authorHILL, N. S.
dc.contributor.authorHIRSCH, R.
dc.contributor.authorHOUWELING, A. C.
dc.contributor.authorHOWARD, L. S.
dc.contributor.authorIVY, D.
dc.contributor.authorKIELY, D. G.
dc.contributor.authorKLINGER, J.
dc.contributor.authorKOVACS, G.
dc.contributor.authorLAHM, T.
dc.contributor.authorLAUDES, M.
dc.contributor.authorMACHADO, R. D.
dc.contributor.authorMACKENZIE ROSS, R. V.
dc.contributor.authorMARSOLO, K.
dc.contributor.authorMARTIN, L. J.
dc.contributor.authorMOLEDINA, S.
dc.contributor.authorMONTANI, D.
dc.contributor.authorNATHAN, S. D.
dc.contributor.authorNEWNHAM, M.
dc.contributor.authorOLSCHEWSKI, A.
dc.contributor.authorOLSCHEWSKI, H.
dc.contributor.authorOUDIZ, R. J.
dc.contributor.authorOUWEHAND, W. H.
dc.contributor.authorPEACOCK, A. J.
dc.contributor.authorPEPKE-ZABA, J.
dc.contributor.authorREHMAN, Z.
dc.contributor.authorROBBINS, I.
dc.contributor.authorRODEN, D. M.
dc.contributor.authorROSENZWEIG, E. B.
dc.contributor.authorSAYDAIN, G.
dc.contributor.authorSCELSI, L.
dc.contributor.authorSCHILZ, R.
dc.contributor.authorSEEGER, W.
dc.contributor.authorSHAFFER, C. M.
dc.contributor.authorSIMMS, R. W.
dc.contributor.authorSIMON, M.
dc.contributor.authorSITBON, O.
dc.contributor.authorSUNTHARALINGAM, J.
dc.contributor.authorTANG, H.
dc.contributor.authorTCHOURBANOV, A. Y.
dc.contributor.authorTHENAPPAN, T.
dc.contributor.authorTORRES, F.
dc.contributor.authorTOSHNER, M. R.
dc.contributor.authorTREACY, C. M.
dc.contributor.authorVONK NOORDEGRAAF, A.
dc.contributor.authorWAISFISZ, Q.
dc.contributor.authorWALSWORTH, A. K.
dc.contributor.authorWALTER, R. E.
dc.contributor.authorWHARTON, J.
dc.contributor.authorWHITE, R. J.
dc.contributor.authorWILT, J.
dc.contributor.authorWORT, S. J.
dc.contributor.authorYUNG, D.
dc.contributor.authorLAWRIE, A.
dc.contributor.authorHUMBERT, M.
dc.contributor.authorSOUBRIER, F.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorPROKOPENKO, I.
dc.contributor.authorKITTLES, R.
dc.contributor.authorGRAF, S.
dc.contributor.authorNICHOLS, W. C.
dc.contributor.authorTREMBATH, R. C.
dc.contributor.authorDESAI, A. A.
dc.contributor.authorMORRELL, N. W.
dc.contributor.authorWILKINS, M. R.
dc.date.accessioned2020-07-20T09:54:56Z
dc.date.available2020-07-20T09:54:56Z
dc.date.issued2019-03
dc.identifier.issn2213-2619 (Electronic) 2213-2600 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/10517
dc.description.abstractEnBACKGROUND: 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 x 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 x 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 x 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, Universite Paris-Sud, and French ANR.
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/us/
dc.subject.enVINTAGE
dc.title.enGenetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis
dc.title.alternativeLancet Respir Meden_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1016/s2213-2600(18)30409-0en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed30527956en_US
bordeaux.journalThe Lancet. Respiratory medicineen_US
bordeaux.page227-238en_US
bordeaux.volume7en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - U1219en_US
bordeaux.issue3en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.exportfalse
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