Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease

Sandra Guauque-Olarte; David Messika-Zeitoun; Arnaud Droit; Maxime Lamontagne; Joël Tremblay-Marchand; Emilie Lavoie-Charland; Nathalie Gaudreault; Benoit J Arsenault; Marie-Pierre Dubé; Jean-Claude Tardif; Simon C Body; Jonathan G Seidman; Catherine Boileau; Patrick Mathieu; Philippe Pibarot; Yohan Bossé

doi:10.1161/CIRCGENETICS.115.001145

Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease

Circ Cardiovasc Genet. 2015 Dec;8(6):812-22. doi: 10.1161/CIRCGENETICS.115.001145. Epub 2015 Nov 9.

Authors

Sandra Guauque-Olarte¹, David Messika-Zeitoun¹, Arnaud Droit¹, Maxime Lamontagne¹, Joël Tremblay-Marchand¹, Emilie Lavoie-Charland¹, Nathalie Gaudreault¹, Benoit J Arsenault¹, Marie-Pierre Dubé¹, Jean-Claude Tardif¹, Simon C Body¹, Jonathan G Seidman¹, Catherine Boileau¹, Patrick Mathieu¹, Philippe Pibarot¹, Yohan Bossé²

Affiliations

¹ 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, Canada (A.D.); Montreal Heart Institute, Department of Medicine (M.-P.D., J.-C.T.), Université de Montréal, Montreal, Canada (B.J.A.); Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA (S.C.B.); and Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.).
² 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, Canada (A.D.); Montreal Heart Institute, Department of Medicine (M.-P.D., J.-C.T.), Université de Montréal, Montreal, Canada (B.J.A.); Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA (S.C.B.); and Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.). yohan.bosse@criucpq.ulaval.ca.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00647088.

Keywords: RNA-Seq; aortic valve calcification; aortic valve stenosis; eQTL; gene expression; genome-wide association study; genomics.

Publication types

Clinical Trial
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aortic Valve / metabolism
Aortic Valve / pathology*
Aortic Valve Stenosis* / genetics
Aortic Valve Stenosis* / metabolism
Calcinosis* / genetics
Calcinosis* / metabolism
Calcium Channels, L-Type* / genetics
Calcium Channels, L-Type* / metabolism
Calcium Signaling / genetics*
Case-Control Studies
Core Binding Factor Alpha 1 Subunit* / genetics
Core Binding Factor Alpha 1 Subunit* / metabolism
Databases, Genetic*
Female
Genome-Wide Association Study
Humans
Male
Polymorphism, Single Nucleotide*

Substances

CACNA1C protein, human
Calcium Channels, L-Type
Core Binding Factor Alpha 1 Subunit
RUNX2 protein, human

Supplementary concepts

Aortic Valve, Calcification of

Associated data