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

TY - JOUR

T1 - A new polymorphism in human calmodulin III gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy.

AU - Friedrich, Felix

AU - Bausero, Pedro

AU - Sun, Yuli

AU - Treszl, András

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

Y1 - 2009

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 Ca(2+) for cardiac contractile function and growth. Any variant that affects CaM expression and/or function may impact on FHC clinical expression. METHODS AND RESULTS: We 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). CONCLUSION: These data suggest that the -34T>A CALM3 polymorphism is a modifier gene for FHC, potentially by affecting expression level of CALM3 and therefore Ca(2+)-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 Ca(2+) for cardiac contractile function and growth. Any variant that affects CaM expression and/or function may impact on FHC clinical expression. METHODS AND RESULTS: We 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). CONCLUSION: These data suggest that the -34T>A CALM3 polymorphism is a modifier gene for FHC, potentially by affecting expression level of CALM3 and therefore Ca(2+)-handling and development of hypertrophy.

M3 - SCORING: Zeitschriftenaufsatz

VL - 30

SP - 1648

EP - 1655

JO - EUR HEART J

JF - EUR HEART J

SN - 0195-668X

IS - 13

M1 - 13

ER -