title: Genetic variation in NCAM1 contributes to left ventricular wall thickness in hypertensive families.
abstract: BACKGROUND
  Left ventricular (LV) mass and related phenotypes are heritable, important predictors of cardiovascular disease, particularly in hypertensive individuals.
  
  
  OBJECTIVE
  Identify genetic predictors of echocardiographic phenotypes in hypertensive families.
  
  
  RESULTS
  A multistage genome-wide association study (GWAS) was conducted in hypertensive-ascertained black families (HyperGEN, stage I; GENOA, stage II); findings were replicated in HyperGEN white families (stage III). Echocardiograms were collected using a common protocol, and participants were genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. The following were analyzed using mixed models adjusted for ancestry: in stages I and II, 1258 and 989 blacks, respectively; and in stage III, 1316 whites. Phenotypes included LV mass, LV internal dimension (LVID), wall thicknesses (posterior [PWT] and intraventricular septum [IVST]), and relative wall thickness (RWT). In stage I, 5 single nucleotide polymorphisms (SNPs) had P≤10(-6). In stage II, 1 SNP (rs1436109; NCAM1 intron 1) replicated with the same phenotype (PWT, P=0.025) in addition to RWT (P=0.032). In stage III, rs1436109 was associated with RWT (P=5.47×10(-4)) and LVID (P=1.86×10(-4)). Fisher combined probability value for all stages was RWT=3.80×10(-9), PWT=3.12×10(-7), IVST=8.69×10(-7), LV mass=2.52×10(-3), and LVID=4.80×10(-4).
  
  
  CONCLUSIONS
  This GWAS conducted in hypertensive families identified a variant in NCAM1 associated with LV wall thickness and RWT. NCAM is upregulated during the remodeling period of hypertrophy to heart failure in Dahl salt-sensitive rats. Our initial screening in hypertensive blacks may have provided the context for this novel locus.
authors.affiliation: Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, RPHB 220E, 1530 3rd Ave South, Birmingham, AL 35294-0022, USA. arnett@uab.edu
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.forename: Kristin J
authors.initials: KJ
authors.lastname: Meyers
authors.forename: Richard B
authors.initials: RB
authors.lastname: Devereux
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.forename: Charles C
authors.initials: CC
authors.lastname: Gu
authors.forename: Laura K
authors.initials: LK
authors.lastname: Vaughan
authors.forename: Rodney T
authors.initials: RT
authors.lastname: Perry
authors.forename: Amit
authors.initials: A
authors.lastname: Patki
authors.forename: Steven A
authors.initials: SA
authors.lastname: Claas
authors.forename: Yan V
authors.initials: YV
authors.lastname: Sun
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Kardia
mesh_terms: D000328:Adult; D000368:Aged; D044383:Black People / Q000208:ethnology / Q000235:genetics; D019002:CD56 Antigen / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000473:pathology*; D006801:Humans; D006973:Hypertension / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D017379:Hypertrophy, Left Ventricular / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014463:Ultrasonography; D044465:White People / Q000208:ethnology / Q000235:genetics
chemical_list: D019002:CD56 Antigen; C522918:NCAM1 protein, human