title: A functional variant in the coding region of CAMTA2 is associated with left ventricular hypertrophy by affecting the activation of Nkx2.5-dependent transcription.
abstract: OBJECTIVE
  The calmodulin-binding transcription activator 2 (CAMTA2) promotes transcription of genes involved in cardiac hypertrophy through its interaction with Nkx2.5 and is an indispensable transcription coactivator for cardiac hypertrophy. We hypothesized that variants in the coding region of CAMTA2 would affect its function and confer a risk of cardiac hypertrophy.
  
  
  METHODS
  The effects of the variant rs238234 on the activity of the atrial natriuretic factor promoter and on the cardiomyocytes hypertrophy were assessed in the H9C2 cell line and primary neonatal rat cardiomyocytes, respectively. Furthermore, the association of this variant with left ventricular hypertrophy (LVH) was tested in hypertensive patients with and without hypertrophy (N = 325 and 697), and this analysis was replicated in an independent population of 987 hypertensive patients without hypertrophy and 463 hypertensive patients with hypertrophy.
  
  
  RESULTS
  We found that the G allele of rs238234 activated the atrial natriuretic factor promoter more strongly than the C allele. The cell size of cardiomyocytes was larger in the presence of the Ad-CAMTA2 G allele, and the G allele was associated with significantly increased susceptibility to LVH in hypertensive [odds ratio (OR), 1.29; P = 0.009]. In the discovery cohort, after adjusting for age and sex, the GG genotype was significantly associated with increased LVH risk (OR, 1.75; P = 0.015). There was little attenuation of the ORs (1.62; P < 0.05) when adjusting for BMI, heart rate, blood pressure, smoking, and drinking and further adjusting all covariates including lipid levels and other major risk factors. However, the GC genotype did not show any association with LVH using three regressive models. Replication in the second study yielded similar results.
  
  
  CONCLUSIONS
  Our results provide evidence that the rs238234 GG genotype in the coding region of CAMTA2 may increase the risk of LVH by affecting the activation of Nkx2.5-dependent transcription.
authors.affiliation: aInternal Medicine bSino-German Laboratory for Molecular Medicine cNational Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China *Wei-hua Song and Ya-hui Lin contributed equally to the writing of this article.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Song
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Lin
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Yin-Hui
authors.initials: YH
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.forename: Li-Bo
authors.initials: LB
authors.lastname: Hou
authors.forename: Chan-Na
authors.initials: CN
authors.lastname: Zhang
authors.forename: Ru-Tai
authors.initials: RT
authors.lastname: Hui
authors.forename: Jing-Zhou
authors.initials: JZ
authors.lastname: Chen
mesh_terms: D000483:Alleles; D044466:Asian People; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002681:China; D003430:Cross-Sectional Studies; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011795:Surveys and Questionnaires; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D002135:Calcium-Binding Proteins; D002148:Calmodulin-Binding Proteins; D000072576:Homeobox Protein Nkx-2.5; C095552:NKX2-5 protein, human; D015534:Trans-Activators