Abstract
Identifying predictors of left ventricular hypertrophy has been an active study topic because of its association with cardiovascular morbidity and mortality. We examined the epistatic effect (gene–gene interaction) of two genes (angiotensin-converting enzyme (ACE) insertion/deletion (I/D); angiotensinogen (AGT) -6G-A, M235T, -20A-C) in the renin–angiotensin system on left ventricular mass (LVM) among hypertensive participants in the Hypertension Genetic Epidemiology Network study. Included were 2156 participants aged 20–87 years (60% women, 63% African American). We employed mixed linear regression models to assess main effects of four genetic variants on echocardigraphically determined LVM (indexed for height), and ACE-by-AGT epistatic effects. There was evidence that AGT -6G-A was associated with LVM among white participants: adjusted mean LVM (gm–2.7) increased with ‘G’ allele copy number (‘AA’:41.2, ‘AG’:42.3, ‘GG’:44.0; P=0.03). There was also evidence of an ACE I/D-by-AGT -20A-C epistatic effect among white participants (interaction P=0.03): among ACE ‘DD’ participants, AGT -20A-C ‘C’ allele carriers had lower mean LVM than ‘AA’ homozygotes (‘DD/CC’:39.2, ‘DD/AC’:39.9, ‘DD/AA’:43.9), with no similar significant effect among ACE ‘I’ allele carriers (‘ID/CC’:47.2, ‘ID/AC’:43.4, ‘ID/AA’:42.6; ‘II/CC’: NA, ‘II/AC’:41.3, ‘II/AA’:43.1). These findings indicate that renin–angiotensin system variants in at least two genes may interact to modulate LVM.
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References
Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP . Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322: 1561–1566.
Savage DD, Levy D, Dannenberg AL, Garrison RJ, Castelli WP . Association of echocardiographic left ventricular mass with body size, blood pressure and physical activity (the Framingham Study). Am J Cardiol 1990; 65: 371–376.
Arnett DK, Hong Y, Bella JN, Oberman A, Kitzman DW, Hopkins PN et al. Sibling correlation of left ventricular mass and geometry in hypertensive African Americans and whites: the HyperGEN study. Hypertension Genetic Epidemiology Network. Am J Hypertens 2001; 14: 1226–1230.
Swan L, Birnie DH, Padmanabhan S, Inglis G, Connell JM, Hillis WS . The genetic determination of left ventricular mass in healthy adults. Eur Heart J 2003; 24: 577–582.
Gharavi AG, Lipkowitz MS, Diamond JA, Jhang JS, Phillips RA . Deletion polymorphism of the angiotensin-converting enzyme gene is independently associated with left ventricular mass and geometric remodeling in systemic hypertension. Am J Cardiol 1996; 77: 1315–1319.
Gomez-Angelats E, de la Sierra A, Enjuto M, Sierra C, Oriola J, Francino A et al. Lack of association between ACE gene polymorphism and left ventricular hypertrophy in essential hypertension. J Hum Hypertens 2000; 14: 47–49.
Karjalainen J, Kujala UM, Stolt A, Mantysaari M, Viitasalo M, Kainulainen K et al. Angiotensinogen gene M235T polymorphism predicts left ventricular hypertrophy in endurance athletes. J Am Coll Cardiol 1999; 34: 494–499.
Kauma H, Ikaheimo M, Savolainen MJ, Kiema TR, Rantala AO, Lilja M et al. Variants of renin-angiotensin system genes and echocardiographic left ventricular mass. Eur Heart J 1998; 19: 1109–1117.
Kuznetsova T, Staessen JA, Thijs L, Kunath C, Olszanecka A, Ryabikov A et al. Left ventricular mass in relation to genetic variation in angiotensin II receptors, renin system genes, and sodium excretion. Circulation 2004; 110: 2644–2650.
Lindpaintner K, Lee M, Larson MG, Rao VS, Pfeffer MA, Ordovas JM et al. Absence of association or genetic linkage between the angiotensin-converting-enzyme gene and left ventricular mass. N Engl J Med 1996; 334: 1023–1028.
Mayet J, O’Kane KP, Elton R, Johnstone HA, Shahi M, Ozkor MA et al. Left ventricular hypertrophy, blood pressure and ACE genotype in untreated hypertension. J Hum Hypertens 1997; 11: 595–597.
Moleda P, Majkowska L, Kaliszczak R, Safranow K, Adler G, Goracy I . Insertion/deletion polymorphism of angiotensin I converting enzyme gene and left ventricular hypertrophy in patients with type 2 diabetes mellitus. Kardiol Pol 2006; 64: 959–965;discussion 966.
Perticone F, Ceravolo R, Cosco C, Trapasso M, Zingone A, Malatesta P et al. Deletion polymorphism of angiotensin-converting enzyme gene and left ventricular hypertrophy in southern Italian patients. J Am Coll Cardiol 1997; 29: 365–369.
Saeed M, Siddiqui S, Khan A, Butt ZA, Parvez SH, Frossard PM . Association of ACE polymorphisms with left ventricular hypertrophy. Neuro Endocrinol Lett 2005; 26: 393–396.
Tang W, Devereux RB, Rao DC, Oberman A, Hopkins PN, Kitzman DW et al. Associations between angiotensinogen gene variants and left ventricular mass and function in the HyperGEN study. Am Heart J 2002; 143: 854–860.
West MJ, Summers KM, Wong KK, Burstow DJ . Renin-angiotensin system gene polymorphisms and left ventricular hypertrophy. The case against an association. Adv Exp Med Biol 1997; 432: 117–122.
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F . An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1343–1346.
Gaillard-Sanchez I, Mattei MG, Clauser E, Corvol P . Assignment by in situ hybridization of the angiotensinogen gene to chromosome band 1q4, the same region as the human renin gene. Hum Genet 1990; 84: 341–343.
Inoue I, Nakajima T, Williams CS, Quackenbush J, Puryear R, Powers M et al. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest 1997; 99: 1786–1797.
Zhao YY, Zhou J, Narayanan CS, Cui Y, Kumar A . Role of C/A polymorphism at -20 on the expression of human angiotensinogen gene. Hypertension 1999; 33: 108–115.
Jeunemaitre XSF, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 1992; 71: 169–180.
Kuznetsova T, Staessen JA, Wang JG, Gasowski J, Nikitin Y, Ryabikov A et al. Antihypertensive treatment modulates the association between the D/I ACE gene polymorphism and left ventricular hypertrophy: a meta-analysis. J Hum Hypertens 2000; 14: 447–454.
Goracy J, Peregud-Pogorzelska M, Goracy I, Kaczmarczyk M, Kornacewicz-Jach Z, Naruszewicz M et al. Allelic variants of genes: angiotensin I-converting enzyme (ACE), angiotensin-II type 1 receptor (AT1R), methylenetetrahydrofolate reductase and left ventricular mass in patients with myocardial infarction. Pol Arch Med Wewn 2006; 115: 105–111.
Perkins MJ, Van Driest SL, Ellsworth EG, Will ML, Gersh BJ, Ommen SR et al. Gene-specific modifying effects of pro-LVH polymorphisms involving the renin-angiotensin-aldosterone system among 389 unrelated patients with hypertrophic cardiomyopathy. Eur Heart J 2005; 26: 2457–2462.
Jeng JR . Left ventricular mass, carotid wall thickness, and angiotensinogen gene polymorphism in patients with hypertension. Am J Hypertens 1999; 12: 443–450.
Kuznetsova T, Staessen JA, Reineke T, Olszanecka A, Ryabikov A, Tikhonoff V et al. Context-dependency of the relation between left ventricular mass and AGT gene variants. J Hum Hypertens 2005; 19: 155–163.
Ott CST, Hilgers KF, Kreutz R, Schlaich MP, Schmieder RE . Left-ventricular structure and function are influenced by angiotensinogen gene polymorphism (-20 A/C) in young male patients. Am J Hypertens 2007; 20: 974–980.
Patel DA, Li S, Chen W, Srinivasan SR, Boerwinkle E, Berenson GS, Bogalusa Heart Study. G-6A polymorphism of the angiotensinogen gene and its association with left ventricular mass in asymptomatic young adults from a biethnic community: the Bogalusa Heart Study. Am J Hypertens 2005; 18: 1137–1141.
Bell JT, Wallace C, Dobson R, Wiltshire S, Mein C, Pembroke J et al. Two-dimensional genome-scan identifies novel epistatic loci for essential hypertension. Hum Mol Genet 2006; 15: 1365–1374.
Cicila GT, Morgan EE, Lee SJ, Farms P, Yerga-Woolwine S, Toland EJ et al. Epistatic genetic determinants of blood pressure and mortality in a salt-sensitive hypertension model. Hypertension 2009; 53: 725–732.
Kardia SL, Bielak LF, Lange LA, Cheverud JM, Boerwinkle E, Turner ST et al. Epistatic effects between two genes in the renin-angiotensin system and systolic blood pressure and coronary artery calcification. Med Sci Monit 2006; 12: CR150–CR158.
Palijan A, Dutil J, Deng AY . Quantitative trait loci with opposing blood pressure effects demonstrating epistasis on Dahl rat chromosome 3. Physiol Genomics 2003; 15: 1–8.
Williams RR, Rao DC, Ellison RC, Arnett DK, Heiss G, Oberman A et al. NHLBI family blood pressure program: methodology and recruitment in the HyperGEN network. Hypertension genetic epidemiology network. Ann Epidemiol 2000; 10: 389–400.
Devereux RB, Lutas EM, Casale PN, Kligfield P, Eisenberg RR, Hammond IW et al. Standardization of M-mode echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol 1984; 4: 1222–1230.
de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH . Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 1995; 25: 1056–1062.
Kim DS, Choi SI, Lee HS, Park JK, Yi HK . Determination of human angiotensin converting enzyme (ACE) gene polymorphisms in erectile dysfunction: frequency differences of ACE gene polymorphisms according to the method of analysis. Clin Chem Lab Med 2001; 39: 11–14.
Russ AP, Maerz W, Ruzicka V, Stein U, Gross W . Rapid detection of the hypertension-associated Met235—>Thr allele of the human angiotensinogen gene. Hum Mol Genet 1993; 2: 609–610.
Jeunemaitre X, Inoue I, Williams C, Charru A, Tichet J, Powers M et al. Haplotypes of angiotensinogen in essential hypertension. Am J Hum Genet 1997; 60: 1448–1460.
Ishigami T, Umemura S, Tamura K, Hibi K, Nyui N, Kihara M et al. Essential hypertension and 5′ upstream core promoter region of human angiotensinogen gene. Hypertension 1997; 30: 1325–1330.
Nakajima T, Wooding S, Sakagami T, Emi M, Tokunaga K, Tamiya G et al. Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world. Am J Hum Genet 2004; 74: 898–916.
Acknowledgements
We acknowledge David R Fermin for his preliminary work on data analysis for this project. This work was supported by the National Heart Lung and Blood Institute at the National Institutes of Health (NHLBI R01-555673 HyperGEN: Genetics of LVH).
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Lynch, A., Tang, W., Shi, G. et al. Epistatic effects of ACE I/D and AGT gene variants on left ventricular mass in hypertensive patients: the HyperGEN study. J Hum Hypertens 26, 133–140 (2012). https://doi.org/10.1038/jhh.2010.131
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DOI: https://doi.org/10.1038/jhh.2010.131
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