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 journalArticle

31 Citations (Scopus)

Abstract

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
Volume30
Issue number13
DOIs
Publication statusPublished - Jul 2009

Fingerprint

Familial Hypertrophic Cardiomyopathy
Modifier Genes
Calmodulin
Genes
Genotype
Mutation
Penetrance
HEK293 Cells
Luciferases
Cardiac Myocytes
Genetic Promoter Regions
Gene Frequency
Hypertrophy
Alleles
Growth
Proteins

Keywords

  • Calcium
  • Cardiomyopathy
  • Genetics
  • Hypertrophy
  • Myocardium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

A new polymorphism in human calmodulin III gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy. / Friedrich, Felix W.; Bausero, Pedro; Sun, Yuli; Treszl, Andras; Krämer, Elisabeth; Juhr, Denise; Richard, Pascale; Wegscheider, Karl; Schwartz, Ketty; Brito, Dulce; Arbustini, Eloisa; Waldenström, Anders; Isnard, Richard; Komajda, Michel; Eschenhagen, Thomas; Carrier, Lucie.

In: European Heart Journal, Vol. 30, No. 13, 07.2009, p. 1648-1655.

Research output: Contribution to journalArticle

Friedrich, FW, Bausero, P, Sun, Y, Treszl, A, Krämer, E, Juhr, D, Richard, P, Wegscheider, K, Schwartz, K, Brito, D, Arbustini, E, Waldenström, A, Isnard, R, Komajda, M, Eschenhagen, T & Carrier, L 2009, 'A new polymorphism in human calmodulin III gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy', European Heart Journal, vol. 30, no. 13, pp. 1648-1655. https://doi.org/10.1093/eurheartj/ehp153
Friedrich, Felix W. ; Bausero, Pedro ; Sun, Yuli ; Treszl, Andras ; Krämer, Elisabeth ; Juhr, Denise ; Richard, Pascale ; Wegscheider, Karl ; Schwartz, Ketty ; Brito, Dulce ; Arbustini, Eloisa ; Waldenström, Anders ; Isnard, Richard ; Komajda, Michel ; Eschenhagen, Thomas ; Carrier, Lucie. / A new polymorphism in human calmodulin III gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy. In: European Heart Journal. 2009 ; Vol. 30, No. 13. pp. 1648-1655.
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abstract = "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.",
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AU - Friedrich, Felix W.

AU - Bausero, Pedro

AU - Sun, Yuli

AU - Treszl, Andras

AU - Krämer, Elisabeth

AU - Juhr, Denise

AU - Richard, Pascale

AU - Wegscheider, Karl

AU - Schwartz, Ketty

AU - Brito, Dulce

AU - Arbustini, Eloisa

AU - Waldenström, Anders

AU - Isnard, Richard

AU - Komajda, Michel

AU - Eschenhagen, Thomas

AU - Carrier, Lucie

PY - 2009/7

Y1 - 2009/7

N2 - 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.

AB - 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.

KW - Calcium

KW - Cardiomyopathy

KW - Genetics

KW - Hypertrophy

KW - Myocardium

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