Publication :
Genetic association analyses highlight IL6, ALPL, and NAV1 as three new susceptibility genes underlying calcific aortic valve stenosis

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Date
2019-10-15
Auteurs
Dina, Christian
Messika-Zeitoun, David
Le Scouarnec, Solena
Boureau, Anne-Sophie
Rigade, Sidwell
Direction de publication
Direction de recherche
Titre de la revue
ISSN de la revue
Titre du volume
Éditeur
American Heart Association
Projets de recherche
Structures organisationnelles
Numéro de revue
Résumé
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.
Description
Revue
Circulation. Genomic and precision medicine, Vol. 12 (10) (2019)
DOI
10.1161/CIRCGEN.119.002617
URL vers la version publiée
Mots-clés
Genome-Wide Association Study , Aortic valve stenosis , Interleukin-6 , Transcriptome
Citation
Type de document
article de recherche