A new polymorphism in human calmodulin III gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy

Felix W. Friedrich, Pedro Bausero, Yuli Sun, Andras Treszl, Elisabeth Krämer, Denise Juhr, Pascale Richard, Karl Wegscheider, Ketty Schwartz, Dulce Brito, Eloisa Arbustini, Anders Waldenström, Richard Isnard, Michel Komajda, Thomas Eschenhagen, Lucie Carrier

Research output: Contribution to journalArticlepeer-review


Aims familial hypertrophic cardiomyopathy (FHC) is caused by mutations in genes encoding sarcomeric proteins. Incomplete penetrance suggests the existence of modifier genes. Calmodulin (CaM) could be of importance given the key role of Ca2+ for cardiac contractile function and growth. Any variant that affects CaM expression and/or function may impact on FHC clinical expression.Methods and resultsWe screened the promoter region of human calmodulin III gene (CALM3) and identified a new -34T>A polymorphism with a T-allele frequency of 0.70. The distribution of CALM3 genotypes differed in 180 unrelated FHC patients carrying a known FHC mutation compared with 134 controls, with higher TT-genotype frequency (0.73 vs. 0.51) and lower frequencies of AT- (0.24 vs. 0.37) and AA genotypes (0.03 vs. 0.11; P = 0.0005). To study whether the -34T>A polymorphism could play a modifier role, patients' relatives including both affected and healthy carriers were added. Affected carriers had a 0.56 times higher odds of carrying a T allele than healthy carriers (P = 0.053). We then investigated whether the -34T>A polymorphism affects the promoter activity using luciferase reporter vectors containing either CALM3-T or CALM3-A promoters. The activity of CALM3-T was lower than CALM3-A in HEK293 cells (1.00 ± 0.19 vs. 2.31 ± 0.13, P = 0.00001) and in cardiomyocytes (0.96 ± 0.10 vs. 1.33 ± 0.08, P = 0.00727).ConclusionThese data suggest that the -34T>A CALM3 polymorphism is a modifier gene for FHC, potentially by affecting expression level of CALM3 and therefore Ca2+-handling and development of hypertrophy.

Original languageEnglish
Pages (from-to)1648-1655
Number of pages8
JournalEuropean Heart Journal
Issue number13
Publication statusPublished - Jul 2009


  • Calcium
  • Cardiomyopathy
  • Genetics
  • Hypertrophy
  • Myocardium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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