title: Genetic associations with valvular calcification and aortic stenosis.
abstract: BACKGROUND
  Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
  
  
  METHODS
  We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
  
  
  RESULTS
  One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently.
  
  
  CONCLUSIONS
  Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).
authors: Department of Medicine and the Research Institute, McGill University Health Centre, Montreal.
authors: George
authors: G
authors: Thanassoulis
authors: Catherine Y
authors: CY
authors: Campbell
authors: David S
authors: DS
authors: Owens
authors: J Gustav
authors: JG
authors: Smith
authors: Albert V
authors: AV
authors: Smith
authors: Gina M
authors: GM
authors: Peloso
authors: Kathleen F
authors: KF
authors: Kerr
authors: Sonali
authors: S
authors: Pechlivanis
authors: Matthew J
authors: MJ
authors: Budoff
authors: Tamara B
authors: TB
authors: Harris
authors: Rajeev
authors: R
authors: Malhotra
authors: Kevin D
authors: KD
authors: O'Brien
authors: Pia R
authors: PR
authors: Kamstrup
authors: Børge G
authors: BG
authors: Nordestgaard
authors: Anne
authors: A
authors: Tybjaerg-Hansen
authors: Matthew A
authors: MA
authors: Allison
authors: Thor
authors: T
authors: Aspelund
authors: Michael H
authors: MH
authors: Criqui
authors: Susan R
authors: SR
authors: Heckbert
authors: Shih-Jen
authors: SJ
authors: Hwang
authors: Yongmei
authors: Y
authors: Liu
authors: Marketa
authors: M
authors: Sjogren
authors: Jesper
authors: J
authors: van der Pals
authors: Hagen
authors: H
authors: Kälsch
authors: Thomas W
authors: TW
authors: Mühleisen
authors: Markus M
authors: MM
authors: Nöthen
authors: L Adrienne
authors: LA
authors: Cupples
authors: Muriel
authors: M
authors: Caslake
authors: Emanuele
authors: E
authors: Di Angelantonio
authors: John
authors: J
authors: Danesh
authors: Jerome I
authors: JI
authors: Rotter
authors: Sigurdur
authors: S
authors: Sigurdsson
authors: Quenna
authors: Q
authors: Wong
authors: Raimund
authors: R
authors: Erbel
authors: Sekar
authors: S
authors: Kathiresan
authors: Olle
authors: O
authors: Melander
authors: Vilmundur
authors: V
authors: Gudnason
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Wendy S
authors: WS
authors: Post
mesh_terms: D000368:Aged; D001021:Aortic Valve / Q000000981:diagnostic imaging / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000000981:diagnostic imaging / Q000208:ethnology / Q000235:genetics*; D002114:Calcinosis / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006349:Heart Valve Diseases / Q000000981:diagnostic imaging / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D017270:Lipoprotein(a) / Q000235:genetics*; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D008943:Mitral Valve / Q000000981:diagnostic imaging / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D014057:Tomography, X-Ray Computed
chemical_list: D017270:Lipoprotein(a)
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