Calmodulin II (CALM2) gene polymorphism might be responsible for the variation in the left ventricular mass amongst healthy individuals. The aim was to evaluate the correlation between left ventricular mass (LVM) and g.474955027G>A (rs7565161) polymorphism adjacent to the CALM2 gene. Healthy Polish newborns (n = 206) were recruited. Two-dimensional M-mode echocardiography was used to assess LVM. Polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism and sequencing analyses. The carriers of the G allele of the CALM2 polymorphism had significantly higher left ventricular mass/weight (LVM/BW) values, when compared with newborns homozygous for the A allele (3.1？g/m2 versus 2.5？g/m2, = 0.036). The AG genotype of CALM2 was associated with the highest values of LVM/BW, exhibiting a pattern of overdominance (2.9？g/kg versus 3.1？g/kg versus 2.5？g/kg, = 0.037). The results of this study suggest that G>A CALM2 polymorphism may account for subtle variation in LVM at birth. 1. Introduction Left ventricular hypertrophy (LVH) and increased left ventricular mass (LVM) are strong risk factors for cardiovascular disease and morbidity [1]. Cardiac hypertrophy is characterized by increased cell size, cardiac remodeling of myofilaments, and increased expression of fetal genes [2]. LVM results from a complex of interaction between genetic, environmental, and lifestyle factors. Increased knowledge concerning genes involved in the modulation of LVM will lead to a better understanding of the etiopathogenesis of LVH. Calcium (Ca2+) is arguably the most important messenger in cardiac muscle and plays a central role in regulating contractility, gene expression, hypertrophy, and apoptosis. It has been well described that Ca2+ transient movements regulate the transcription and gene expression that characterize the hypertrophic response of cardiomyocytes [2, 3]. The levels of Ca2+ are precisely controlled. A major sensor and mediator of intracellular Ca2+ transient movements is calmodulin (CaM). The Ca2+CaM complex binds and activates enzymes, including protein kinases, protein phosphatases, phospholipases, nitric oxide synthases, and endonucleases. Three Ca2+ calmodulin dependent enzymes have significant roles in cardiac function: Ca2+ calmodulin-dependent protein kinase (CaMK), protein phosphatase 2B (calcineurin, CaN), and myosin light-chain kinase (MLCK). CaMK and CaN have been shown to play key and often synergistic roles in transcriptional regulation in cardiomyocytes [4]. It has been suggested that CaMK regulates gene expression via
References
[1]
D. Levy, R. J. Garrison, D. D. Savage, W. B. Kannel, and W. P. Castelli, “Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study,” The New England Journal of Medicine, vol. 322, no. 22, pp. 1561–1566, 1990.
[2]
N. Frey and E. N. Olson, “Cardiac hypertrophy: the good, the bad, and the ugly,” Annual Review of Physiology, vol. 65, pp. 45–79, 2003.
[3]
G. E. Hardingham and H. Bading, “Nuclear calcium: a key regulator of gene expression,” BioMetals, vol. 11, no. 4, pp. 345–358, 1998.
[4]
R. Passier, H. Zeng, N. Frey et al., “CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo,” Journal of Clinical Investigation, vol. 105, no. 10, pp. 1395–1406, 2000.
[5]
H. L. Sweeney, B. F. Bowman, and J. T. Stull, “Myosin light chain phosphorylation in vertebrate striated muscle: regulation and function,” American Journal of Physiology, vol. 264, no. 5, pp. C1085–C1095, 1993.
[6]
P. Ding, J. Huang, P. K. Battiprolu, J. A. Hill, K. E. Kamm, and J. T. Stull, “Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo,” Journal of Biological Chemistry, vol. 285, no. 52, pp. 40819–40829, 2010.
[7]
A. P. Braun and H. Schulman, “The multifunctional calcium/calmodulin-dependent protein kinase: from form to function,” Annual Review of Physiology, vol. 57, pp. 417–445, 1995.
[8]
B. Li, J. R. Dedman, and M. A. Kaetzel, “Nuclear Ca2+/calmodulin-dependent protein kinase II in the murine heart,” Biochimica et Biophysica Acta, vol. 1763, no. 11, pp. 1275–1281, 2006.
[9]
T. Zhang, L. S. Maier, N. D. Dalton et al., “The isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure,” Circulation Research, vol. 92, no. 8, pp. 912–919, 2003.
[10]
D. Hagemann, J. Bohlender, B. Hoch, E.-G. Kraus, and P. Karczewski, “Expression of Ca2+/calmodulin-dependent protein kinase II δ-subunit isoforms in rats with hypertensive cardiac hypertrophy,” Molecular and Cellular Biochemistry, vol. 220, no. 1-2, pp. 69–76, 2001.
[11]
T. Zhang and J. H. Brown, “Role of Ca2+/calmodulin-dependent protein kinase II in cardiac hypertrophy and heart failure,” Cardiovascular Research, vol. 63, no. 3, pp. 476–486, 2004.
[12]
T. Zhang, E. N. Johnson, Y. Gu et al., “The cardiac-specific nuclear δB isoform of Ca2+/calmodulin-dependent protein kinase II induces hypertrophy and dilated cardiomyopathy associated with increased protein phosphatase 2A activity,” Journal of Biological Chemistry, vol. 277, no. 2, pp. 1261–1267, 2002.
[13]
K. E. Fladmark, O. T. Brustugun, G. Mellgren et al., “Ca2+/calmodulin-dependent protein kinase II is required for microcystin-induced apoptosis,” Journal of Biological Chemistry, vol. 277, no. 4, pp. 2804–2811, 2002.
[14]
H. Mototani, A. Iida, Y. Nakamura, and S. Ikegawa, “Identification of sequence polymorphisms in CALM2 and analysis of association with hip osteoarthritis in a Japanese population,” Journal of Bone and Mineral Metabolism, vol. 28, no. 5, pp. 547–553, 2010.
[15]
T. Liu, L. Xie, J. Ye, Y. Liu, and X. He, “Screening of candidate genes for primary open angle glaucoma,” Molecular Vision, vol. 18, pp. 2119–2126, 2012.
[16]
R. S. Vasan, N. L. Glazer, J. F. Felix, et al., “Genetic variants associated with cardiac structur and function,” JAMA, vol. 302, no. 2, pp. 168–178, 2009.
[17]
R. D. Mosteller, “Simplified calculation of body-surface area,” The New England Journal of Medicine, vol. 317, no. 17, p. 1098, 1987.
[18]
F. U. Huwez, A. B. Houston, J. Watson, S. McLaughin, and P. W. Macfarlane, “Age and body surface area related normal upper and lower limits of M mode echocardiographic measurements and left ventricular volume and mass from infancy to early adulthood,” British Heart Journal, vol. 72, no. 3, pp. 276–280, 1994.
[19]
H. A. Verhaaren, R. M. Schieken, M. Mosteller, J. K. Hewitt, L. J. Eaves, and W. E. Nance, “Bivariate genetic analysis of left ventricular mass and weight in pubertal twins (The Medical College of Virginia Twin Study),” American Journal of Cardiology, vol. 68, no. 6, pp. 661–668, 1991.
[20]
L. Swan, D. H. Birnie, S. Padmanabhan, G. Inglis, J. M. C. Connell, and W. S. Hillis, “The genetic determination of left ventricular mass in healthy adults,” European Heart Journal, vol. 24, no. 6, pp. 577–582, 2003.
[21]
P. Sharma, R. P. S. Middelberg, T. Andrew, M. R. Johnson, H. Christley, and M. J. Brown, “Heritability of left ventricular mass in a large cohort of twins,” Journal of Hypertension, vol. 24, no. 2, pp. 321–324, 2006.
[22]
J. N. Bella, J. W. MacCluer, M. J. Roman et al., “Heritability of left ventricular dimensions and mass in American Indians: the Strong Heart Study,” Journal of Hypertension, vol. 22, no. 2, pp. 281–286, 2004.
[23]
T. L. Assimes, B. Narasimhan, T. B. Seto et al., “Heritability of left ventricular mass in Japanese families living in Hawaii: the SAPPHIRe study,” Journal of Hypertension, vol. 25, no. 5, pp. 985–992, 2007.
[24]
L. Li, K. Lu, Z. Chen, T. Mu, Z. Hu, and X. Li, “Dominance, overdominance and epistasis condition the heterosis in two heterotic rice hybrids,” Genetics, vol. 180, no. 3, pp. 1725–1742, 2008.
[25]
K. J. Meyers, T. H. Mosley, E. Fox et al., “Genetic variations associated with echocardiographic left ventricular traits in hypertensive blacks,” Hypertension, vol. 49, no. 5, pp. 992–999, 2007.
[26]
A. Santovito, P. Cervella, D. Schleicherova, and M. Delpero, “Genotyping for cytokine polymorphisms in a Northern Ivory Coast population reveals a high frequency of the heterozygote genotypes for the TNF-α-308G/A SNP,” International Journal of Immunogenetics, 2012.
[27]
G. Y. Miasnikova, A. I. Sergueeva, M. Nouraie et al., “The heterozygote advantage of the chuvash polycythemia mutation may be protection against anemia,” Haematologica, vol. 96, no. 9, pp. 1371–1374, 2011.
[28]
D. Sellis, B. J. Callahan, D. A. Petrov, and P. W. Messer, “Heterozygote advantage as a natural consequence of adaptation in diploids,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 51, pp. 20666–20671, 2011.
[29]
G. C. Williams, “Plejotropy, natural selection and the evolution of senescence,” Evolution, vol. 11, pp. 398–411, 1957.
[30]
S. Chang, T. A. McKinsey, C. L. Zhang, J. A. Richardson, J. A. Hill, and E. N. Olson, “Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development,” Molecular and Cellular Biology, vol. 24, no. 19, pp. 8467–8476, 2004.
[31]
J. D. Molkentin, J.-R. Lu, C. L. Antos et al., “A calcineurin-dependent transcriptional pathway for cardiac hypertrophy,” Cell, vol. 93, no. 2, pp. 215–228, 1998.
[32]
A. K. S. Ho, K. Shang, and R. Duffield, “Calmodulin regulation of the cholinergic receptor in the rat heart during ontogeny and senescence,” Mechanisms of Ageing and Development, vol. 36, no. 2, pp. 143–154, 1986.
[33]
C. D. Rasmussen and A. R. Means, “Calmodulin is involved in regulation of cell proliferation,” The EMBO Journal, vol. 6, no. 13, pp. 3961–3968, 1987.
[34]
A. M. Gillett, M. J. Wallace, M. T. Gillespie, and S. B. Hooper, “Increased expansion of the lung stimulates calmodulin 2 expression in fetal sheep,” American Journal of Physiology, vol. 282, no. 3, pp. L440–L447, 2002.
[35]
S. L. Toutenhoofd, D. Foletti, R. Wicki et al., “Characterization of the human CALM2 calmodulin gene and comparison of the transcriptional activity of CALM1, CALM2 and CALM3,” Cell Calcium, vol. 23, no. 5, pp. 323–338, 1998.
[36]
J. Colomer, N. Agell, P. Engel, and O. Bachs, “Expression of calmodulin and calmodulin binding proteins in lymphoblastoid cells,” Journal of Cellular Physiology, vol. 159, no. 3, pp. 542–550, 1994.
[37]
I. Gor？cy, G. Dawid, B. ？oniewska, J. Gor？cy, and A. Ciechanowicz, “Genetics of the rennin-angitensin system with respect to cardiac and blood pressure phenotypes in healthy newborns infants,” Journal of Renin-Angiotensin-Aldosterone System.
[38]
I. Gor？cy, K. Safranow, and G. Dawid, “Common genetic variants of BMP4, BMPR1A, BMPR1B and ACVR1 genes, left ventricular mass and other parameters of heart in newborns,” Genetic Testing Molecular Biomarkerks, vol. 16, no. 11, pp. 1309–1316, 2012.
[39]
Y. S. Cho, M. J. Go, Y. J. Kim et al., “A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits,” Nature Genetics, vol. 41, no. 5, pp. 527–534, 2009.
[40]
C. Newton-Cheh, T. Johnson, V. Gateva, et al., “Genome-wide association study identifies eight loci associated with blood pressure,” Nature Genetics, vol. 41, no. 6, pp. 666–675, 2009.
[41]
D. Levy, G. B. Ehret, K. Rice, et al., “Genome-wide association study of blood pressure and hypertension,” Nature Genetics, vol. 41, no. 6, pp. 677–687, 2009.
[42]
T. Usui, M. Okada, Y. Hara, and H. Yamawaki, “Exploring calmodulin-related proteins, which mediate development of hypertension, in vascular tissues of spontaneous hypertensive rats,” Biochemical and Biophysical Research Communications, vol. 405, no. 1, pp. 47–51, 2011.
[43]
H. Li, W. Li, A. K. Gupta, P. J. Mohler, M. E. Anderson, and I. M. Grumbach, “Calmodulin kinase II is required for angiotensin II-mediated vascular smooth muscle hypertrophy,” American Journal of Physiology, vol. 298, no. 2, pp. H688–H698, 2010.
