European Heart Journal Advance Access originally published online on May 8, 2009
European Heart Journal 2009 30(13):1648-1655; doi:10.1093/eurheartj/ehp153
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A new polymorphism in human calmodulin III gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy
1 Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2 Inserm, U582, Inserm U974, CNRS UMR7215, Institut de Myologie, Paris F-75013, France
3 UPMC Univ Paris 06, IFR14, Paris F-75013, France
4 Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
5 UF Cardiogénétique et Myogénétique, Groupe Hospitalier Pitié-Salpêtrière, Paris F-75013, France
6 Clínica Universitária de Cardiologia, Faculdade de Medicina de Lisboa, Lisboa, Portugal
7 Centre for Inherited Cardiovascular Diseases, IRCCS Policlinico San Matteo, Pavia, Italy
8 Department of Cardiology, Heart Centre, Umeå University Hospital, Umeå, Sweden
9 Inserm, U621, Paris F-75013, France
10 Institut de Cardiologie, Paris F-75013, France
11 Inserm, U956, Paris F-75013, France
Received 7 October 2008; revised 15 February 2009; accepted 17 March 2009; online publish-ahead-of-print 8 May 2009.
* Corresponding author. Tel: +49 40 7410 57208, Fax: +49 40 7410 55925, Email: l.carrier{at}uke.uni-hamburg.de
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 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 Ca2+-handling and development of hypertrophy.
Key Words: Calcium • Cardiomyopathy • Hypertrophy • Genetics • Myocardium
Deceased on 25 December 2007.
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