Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease
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Background—: Calcific aortic valve stenosis (AS) is a life-threatening disease with no medical therapy. The genetic architecture of AS remains elusive. This study combines genome-wide association studies, gene expression, and expression quantitative trait loci mapping in human valve tissues to identify susceptibility genes of AS. Methods and Results—: A meta-analysis was performed combining the results of 2 genome-wide association studies in 474 and 486 cases from Quebec City (Canada) and Paris (France), respectively. Corresponding controls consisted of 2988 and 1864 individuals with European ancestry from the database of genotypes and phenotypes. mRNA expression levels were evaluated in 9 calcified and 8 normal aortic valves by RNA sequencing. The results were integrated with valve expression quantitative trait loci data obtained from 22 AS patients. Twenty-five single-nucleotide polymorphisms had P <5×10 −6 in the genome-wide association studies meta-analysis. The calcium signaling pathway was the top gene set enriched for genes mapped to moderately AS-associated single-nucleotide polymorphisms. Genes in this pathway were found differentially expressed in valves with and without AS. Two single-nucleotide polymorphisms located in RUNX2 (runt-related transcription factor 2), encoding an osteogenic transcription factor, demonstrated some association with AS (genome-wide association studies P =5.33×10 −5 ). The mRNA expression levels of RUNX2 were upregulated in calcified valves and associated with eQTL-SNPs. CACNA1C encoding a subunit of a voltage-dependent calcium channel was upregulated in calcified valves. The eQTL-SNP with the most significant association with AS located in CACNA1C was associated with higher expression of the gene. Conclusions—: This integrative genomic study confirmed the role of RUNX2 as a potential driver of AS and identified a new AS susceptibility gene, CACNA1C , belonging to the calcium signaling pathway.
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A genome-wide association study identified variants in RUNX2 and CACNA1C associated with calcific AS and found they upregulate their respective mRNA levels.
“Recently, a study has identified in a genome wide association study that variants located in RUNX2 and CACNA1C, which encodes for an osteogenic transcription factor and a voltage-dependent calcium channel subunit respectively, were associated with calcific AS and were found to upregulate their respective mRNA levels.150”
From Calcific aortic stenosis (2016) · cites this paper as [150]
The Results (GWAS Results and Integration With Valve eQTL Mapping; page unavailable) report variants moderately associated with aortic stenosis in both genes, but none reached genome-wide significance. A CACNA1C risk allele was associated with higher CACNA1C mRNA; the AS-associated RUNX2 variants were not evaluated for an expression effect, and separate RUNX2 expression-associated variants were independent of them. The claim therefore overstates both the strength of the GWAS findings and the evidence that the RUNX2 risk variants upregulate mRNA. (LLM, conf=0.92)
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- Authors
- Guauque-Olarte, S., Messika-Zeitoun, D., Droit, A., Lamontagne, M., Tremblay-Marchand, J., Lavoie-Charland, E., Gaudreault, N., Arsenault, B. J., Dubé, M.-P., Tardif, J.-C., Body, S. C., Seidman, J. G., Boileau, C., Mathieu, P., Pibarot, P., & Bossé, Y.
- Affiliations
- Brigham and Women's Hospital (US)
- From the Centre de recherche Institut universitaire de cardiologie et de pneumologie de Québec, Quebec, Canada (S.G.-O., M.L., J.T.-M., E.L.-C., N.G., P.M., P.P., Y.B.); Departments of Molecular Medicine (A.D., Y.B.), Surgery (P.M.), and Medicine (P.P.), Laval University, Quebec, Canada; Cardiology Department, AP-HP, Bichat Hospital, Paris, France (D.M.-Z.); INSERM U698, Paris, France (D.M.-Z.); Département de Génétique, Hôpital Bichat, 75018 Paris, France (C.B.); Centre de Recherche du CHUQ, Quebec...
- ORCID
- Venue
- Circulation: Cardiovascular Genetics
- Published
- 2015-12
- Volume
- 8
- Issue
- 6
- Pages
- 812-822
- ISSN
- 1942-325X (ISSN-L)
- 1942-3268
- PMC
- PMC4934886
- OpenAlex
- W2174239754
- Cited by
- 72
- References
- 47
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 12 · 2021: 10 · 2020: 8 · 2019: 3 · 2018: 8 · 2017: 8 · 2016: 3
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Cardiovascular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Corpus Université Laval (Université Laval) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-245048, MOP102481, MOP79342, MOP137058)
- National Heart, Lung, and Blood Institute (R01HL114823)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- calcific aortic stenosis, Runx2, CACNA1C, calcium signaling, genetic susceptibility, single nucleotide polymorphisms, expression quantitative trait loci, voltage-gated calcium channels, osteogenic transcription factors
- MeSH terms
- Aortic Valve, Aortic Valve Stenosis, Calcinosis, Female, Humans, Male, Case-Control Studies, Calcium Signaling, Polymorphism, Single Nucleotide, Calcium Channels, L-Type, Databases, Genetic, Core Binding Factor Alpha 1 Subunit, Genome-Wide Association Study
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