| Title: | Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis |
| Journal: | Circulation Genomic and Precision Medicine |
| Published: | 15 Oct 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32141789/ |
| DOI: | https://doi.org/10.1161/circgen.119.002617 |
| URL: | https://www.biorxiv.org/content/biorxiv/early/2019/01/14/515494.full.pdf |
Publication 4896
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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.</p>
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.</p>
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.</p>
CONCLUSIONS: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.</p>
11 Keywords
- Alkaline Phosphatase
- Aortic Valve
- Aortic Valve Stenosis
- Calcinosis
- Cohort Studies
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Interleukin-6
- Microtubule-Associated Proteins
- Polymorphism, Single Nucleotide
51 Authors
- Sébastien Thériault
- Christian Dina
- David Messika-Zeitoun
- Solena Le Scouarnec
- Romain Capoulade
- Nathalie Gaudreault
- Sidwell Rigade
- Zhonglin Li
- Floriane Simonet
- Maxime Lamontagne
- Marie-Annick Clavel
- Benoit J. Arsenault
- Anne-Sophie Boureau
- Simon Lecointe
- Estelle Baron
- Stéphanie Bonnaud
- Matilde Karakachoff
- Eric Charpentier
- Imen Fellah
- Jean-Christian Roussel
- Jean Philippe Verhoye
- Christophe Baufreton
- Vincent Probst
- Ronan Roussel
- Richard Redon
- François Dagenais
- Philippe Pibarot
- Patrick Mathieu
- Thierry Le Tourneau
- Yohan Bossé
- Jean-Jacques Schott
- B. Balkau
- P. Ducimetière
- E. Eschwège
- F. Alhenc-Gelas
- A. Girault
- F. Fumeron
- M. Marre
- F. Bonnet
- A. Bonnefond
- P. Froguel
- F. Rancière
- J. Cogneau
- C. Born
- E. Caces
- M. Cailleau
- O Lantieri
- J.G. Moreau
- F. Rakotozafy
- J. Tichet
- S. Vol
1 Application
| Application ID | Title |
|---|---|
| 25205 | Identification and characterization of functional variants with a causal role in chronic cardiopulmonary diseases |
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