title: Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Sandra
authors.initials: S
authors.lastname: Guauque-Olarte
authors.affiliation: 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.).
authors.forename: David
authors.initials: D
authors.lastname: Messika-Zeitoun
authors.affiliation: 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.).
authors.forename: Arnaud
authors.initials: A
authors.lastname: Droit
authors.affiliation: 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.).
authors.forename: Maxime
authors.initials: M
authors.lastname: Lamontagne
authors.affiliation: 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.).
authors.forename: Joël
authors.initials: J
authors.lastname: Tremblay-Marchand
authors.affiliation: 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.).
authors.forename: Emilie
authors.initials: E
authors.lastname: Lavoie-Charland
authors.affiliation: 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.).
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaudreault
authors.affiliation: 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.).
authors.forename: Benoit J
authors.initials: BJ
authors.lastname: Arsenault
authors.affiliation: 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.).
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.affiliation: 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.).
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: 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.).
authors.forename: Simon C
authors.initials: SC
authors.lastname: Body
authors.affiliation: 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.).
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: 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.).
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.affiliation: 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.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
authors.affiliation: 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.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Pibarot
authors.affiliation: 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.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
mesh_terms: D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000235:genetics / Q000378:metabolism; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D016022:Case-Control Studies; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human
keywords: RNA-Seq; aortic valve calcification; aortic valve stenosis; eQTL; gene expression; genome-wide association study; genomics