Sébastien Thériault1,2, Christian Dina3, David Messika-Zeitoun4,5,6, Solena Le Scouarnec3, Romain Capoulade1,3,7, Nathalie Gaudreault1, Sidwell Rigade3, Zhonglin Li1, Floriane Simonet3,7, Maxime Lamontagne1, Marie-Annick Clavel1,8, Benoit J Arsenault1,8, Anne-Sophie Boureau3,7, Simon Lecointe3,7, Estelle Baron3, Stéphanie Bonnaud3,7, Matilde Karakachoff3,7, Eric Charpentier3,7, Imen Fellah3,7, Jean-Christian Roussel3,7,9, Jean Philippe Verhoye10, Christophe Baufreton11, Vincent Probst3,7, Ronan Roussel12,13,14, Richard Redon3,7, François Dagenais15, Philippe Pibarot1,8, Patrick Mathieu1, Thierry Le Tourneau3,7, Yohan Bossé1,16, Jean-Jacques Schott3,7. 1. Institut universitaire de cardiologie et de pneumologie de Québec (S.T., R.C., N.G., Z.L., M.L., M.-A.C., B.J.A., P.P., P.M., Y.B.), Laval University, Quebec City, Canada. 2. Department of Molecular Biology, Medical Biochemistry and Pathology (S.T.), Laval University, Quebec City, Canada. 3. l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France (C.D., S.L.S., R.C., S.R., F.S., A.-S.B., S.L., E.B., S.B., M.K., E.C., I.F., J.-C.R., V.P., R. Redon, T.L.T., J.-J.S.). 4. Cardiology Department, AP-HP, Bichat Hospital (D.M.-Z.), Univ Paris 7, France. 5. INSERM U698 (D.M.-Z.), Univ Paris 7, France. 6. Division of Cardiology, University of Ottawa Heart Institute, ON, Canada (D.M.-Z.). 7. l'institut du thorax, CHU Nantes, Nantes, France (R.C., F.S., A.-S.B., S.L., S.B., M.K., I.F., J.-C.R., V.P., R. Redon, T.L.T., J.-J.S.), Hopital Pontchaillou, Inserm 1099, Rennes. 8. Department of Medicine, (M.-A.C., B.J.A., P.P.), Laval University, Quebec City, Canada. 9. Service de chirurgie Thoracique et CardioVasculaire, CHU Nantes (J.-C.R.), Hopital Pontchaillou, Inserm 1099, Rennes. 10. Service de chirurgie cardio vasculaire (J.P.V.), Hopital Pontchaillou, Inserm 1099, Rennes. 11. Service de chirurgie cardiovasculaire, Angers (C.B.). 12. Inserm U1138, Centre de Recherche des Cordeliers (R. Roussel). 13. University Paris Diderot, Paris University (R. Roussel). 14. Diabetology, Endocrinology & Nutrition Department, DHU FIRE, Hopital Bichat, AP-HP, Paris (R. Roussel). 15. Department of Surgery (F.D.), Laval University, Quebec City, Canada. 16. Department of Molecular Medicine (Y.B.), Laval University, Quebec City, Canada.
Abstract
BACKGROUND: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD, have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. METHODS: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. RESULTS: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. CONCLUSIONS: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.
BACKGROUND: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD, have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. METHODS: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. RESULTS: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. CONCLUSIONS: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.
Entities:
Keywords:
Genome-Wide Association Study; aortic valve stenosis; interleukin-6; transcriptome
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