Abstract
Cardiovascular disease remains the leading cause of death worldwide. In this review, we briefly summarize new insights on the modulation of genetic cardiovascular risk by host factors such as sex and age and lifestyle factors such as salt intake. As phenotypes (genotypes) of interest, we considered left ventricular structure and function (ADD1 Gly460Trp; AGTR2 G1675A; ACE D/I), the incidence of heart failure (ADD1 Gly460Trp), heart rate variability (CYP11B2 C-344T; AGTR1 A1166C), carotid distensibility (IL6 G-174C), and serum lipid levels (APOE ɛ 2/ ɛ 3/ ɛ 4; APOA1 A 75G). In each case, the associations with the genetic cardiovascular risk factor were modulated by sex, age, sodium intake, or a combination thereof. These interactions highlight that genetic risk factors and phenotype-genotype associations can only be interpreted within their ecogenetic context. Perhaps a better understanding of these phenomena will lead researchers to target in a more specific way the pathophysiologic mechanisms operating within each individual.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References and Recommended Reading
Murray CJ, Lopez AD: Mortality by cause for eight regions of the world: Global burden of disease study. Lancet 1997, 349:1269–1276.
Mansour-Chemaly M, Haddy N, Siest G, Visvikis S: Family studies: their role in the evaluation of genetic cardiovascular risk factors. Clin Chem Lab Med 2002, 40:1085–1096.
Staessen JA, Wang J, Bianchi G, Birkenhäger WH: Essential hypertension. Lancet 2003, 361:1629–1641.
Sing CF, Stengard JH, Kardia SL: Genes, environment, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003, 23:1190–1196.
Solomon TP, Sistrun SN, Krishnan RK, et al.: Exercise and diet enhance fat oxidation and reduce insulin resistance in older obese adults. J Appl Physiol 2008, 104:1313–1319.
Whelton PK, Appel LJ, Espeland MA, et al.: Sodium reduction and weight loss in the treatment of hypertension in older persons. A randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA 1998, 279:839–846.
Beretta-Piccoli C, Weidmann P, Brown JJ, et al.: Body sodium and blood volume state in essential hypertension: abnormal relation of exchangeable sodium to age and blood pressure in male patients. J Cardiovasc Pharmacol 1984, 6(Suppl 1):S134–S142.
Schmieder RE, Sch⇂hinger H, Messerli FH: Accelerated decline in renal perfusion with aging in essential hypertension. Hypertension 1994, 23:351–357.
Aviv A: Chronobiology versus biology. Telomeres, essential hypertension, and vascular aging. Hypertension 2002, 40:229–232.
Li Y, Thijs L, Kuznetsova T, et al.: Cardiovascular risk in relation to alpha-adducin Gly460Trp polymorphism and systolic pressure. A prospective population study. Hypertension 2005, 46:527–532.
Li Y, Zagato L, Kuznetsova T, et al.: Angiotensinconverting enzyme I/D and alpha-adducin Gly460Trp polymorphisms. From angiotensin-converting enzyme activity to cardiovascular outcome. Hypertension 2007, 49:1291–1297.
Ferrandi M, Bianchi G: Genetic mechanisms underlying the regulation of urinary sodium excretion and arterial blood pressure: the role of adducin. Acta Physiol Scand 2000, 168:187–193.
Bianchi G, Tripodi G, Casari G, et al.: Two point mutations within the adducin genes are involved in blood pressure variation. Proc Natl Acad Sci U S A 1994, 91:3999–4003.
Tripodi G, Valtorta F, Torielli L, et al.: Hypertensionassociated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport. J Clin Invest 1996, 97:2815–2822.
Barlassina C, Schork NJ, Manuta P, et al.: Synergistic effect of alpha-adducin and ACE genes causes blood pressure changes with body sodium and volume expansion. Kidney Int 2000, 57:1083–1090.
Staessen JA, Wang JG, Brand E, et al.: Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population. J Hypertens 2001, 19:1349–1358.
Wang JG, Staessen JA, Tizzoni L, et al.: Renal function in relation to three candidate genes. Am J Kidney Dis 2001, 38:1158–1168.
Harris JR, Pedersen NL, McClearn GE, et al.: Age differences in genetic and environmental infl uences for health from the Swedish Adoption/Twin Study of aging. J Gerontol 1992, 47:213–220.
Kuznetsova T, Citterio L, Herbots L, et al.: Effects of genetic variation in adducin on left ventricular diastolic function as assessed by tissue Doppler imaging in a Flemish population. J Hypertens 2008, 26:1229–1236.
Partridge L, Gems D: Mechanisms of ageing: public or private? Nat Rev Genet 2002, 3:165–175.
Efendiev R, Krmar RT, Ogimoto G, et al.: Hypertensionlinked mutation in the adducin alpha-subunit leads to higher AP2-mu2 phosphorylation and impaired Na+,K+-ATPase trafficking in response to GPCR signals and intracellular sodium. Circ Res 2004, 45:331–340.
Blaustein MP, Lederer WJ: Sodium/calcium exchange: its physiological implications. Physiol Rev 1999, 79:763–854.
Blackburn EH: Telomere states and cell fates. Nature 2000, 408:53–56.
Wong JM, Collins K: Telomere maintenance and disease. Lancet 2003, 362:983–988.
Slagboom PE, Droog S, Boomsma DI: Genetic determination of telomere size in humans: a twin study of three age groups. Am J Hum Genet 1994, 55:876–882.
Serrano AL, Andres V: Telomeres and cardiovascular disease. Does size matter? Circ Res 2004, 94:575–584.
Nawrot T: Role of smoking, oxidative stress and the −174G/ C interleukin-6 polymorphism in biological and vascular ageing. In Genetic Variation and Environmental Factors in Biological and Arterial Ageing. Edited by Nawrot T. Leuven: Acta Biomedica Lovaniense; 2005: 56–69.
Rossouw JE: Hormones, genetic factors, and gender differences in cardiovascular disease. Cardiovasc Res 2002, S3:SS0–SS7.
Pilote L, Dasgupta K, Guru V, et al.: A comprehensive view of sex-specifi c issues related to cardiovascular disease. CMAJ 2007, 176:S1–S44. (Published erratum appears in CMAJ 2007, 176:1310.)
Ordovas JM: Gender, a significant factor in the cross talk between genes, environment, and health. Gend Med 2007, 4(Suppl B):S111–S121.
Beisiegel U, Weber W, Ihrke G, et al.: The LDL receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature 1989, 341:162–164.
Ordovas JM, Litwack-Klein L, Wilson PW, et al.: Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. J Lipid Res 1987, 28:371–380.
Lahoz C, Schaefer EJ, Cupples LA, et al.: Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study. Atherosclerosis 2001, 154:529–537.
Frikke-Schmidt R, Tybjaerg-Hansen A, Steffensen R, et al.: Apolipoprotein E genotype: epsilon32 women are protected while epsilon43 and epsilon44 men are susceptible to ischemic heart disease: the Copenhagen City Heart Study. J Am Coll Cardiol 2000, 35:1192–1199.
Segrest JP, Li L, Anantharamaiah GM, et al.: Structure and function of apolipoprotein A-I and high density lipoprotein. Curr Opin Lipidol 2000, 11:105–115.
Karathanasis SK: Apolipoprotein multigene family: tandem organization of human apolipoprotein A-I, C-III and A-IV genes. Proc Natl Acad Sci U S A 1985, 82:6374–6378.
Lai CO, Parnell LD, Ordovas JM: The APOA1/C3/A4/AS gene cluster, lipid metabolism and cardiovascular disease risk. Curr Opin Lipidol 2005, 16:153–166.
Miller M, Zhan M: Genetic determinants of low highdensity lipoprotein cholesterol. Curr Opin Cardiol 2004, 19:380–384.
Juo SH, Wyszynski DF, Beaty TH, et al.: Mild association between the A/G polymorphism in the promoter of the apolipoprotein A-I gene and apolipoprotein A-I levels: A meta-analysis. Am J Med Genet 1999, 82:235–241.
Ordovas JM, Corella D, Cupples LA, et al.: Polyunsaturated fatty acids modulate the effects of the APOA1 G-A polymorphism on HDL-cholesterol concentrations in a sex-specific manner: the Framingham Study. Am J Clin Nutr 2002, 75:38–46.
Petersen L, Andersen PK, Søensen TI: Genetic and environmental effects on mortality before age 70 years. Epidemiology 2008, 19:472–476.
Dzau VJ: Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med 1993, 153:937–942.
De Gasparo M, Catt KJ, Inagami T, et al.: International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 2000, 52:415–472.
Warnecke C, Mugrauer P, Surder D, et al.: Intronic ANG II type 2 receptor gene polymorphism 1675 G/A modulates receptor protein expression but not mRNA splicing. Am J Physiol Regul Integr Comp Physiol 2005, 289:R1729–1735.
Ozono R, Wang ZQ, Moore AF, et al.: Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney. Hypertension 1997, 30:1238–1246.
Kuznetsova T, Staessen JA, Thijs L, 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.
Kuznetsova T, Staessen JA, Stolarz K, et al.: Relationship of left ventricular mass and the ACE D/I polymorphism varies according to sodium intake. J Hypertens 2004, 22:287–295.
DiBona GF: Nervous kidney. Interaction between renal sympathetic nerves and the renin-angiotensin system in the control of renal function. Hypertension 2000, 36:1083–1088.
Stolarz K, Staessen JA, Kawecka-Jaszcz K, et al.: Genetic variation in CYP11B2 and ATR1 influences heart rate variability conditional on sodium excretion. Hypertension 2004, 44:156–162.
Veglio F, Melchio R, Rabbia F, et al.: Spectral characteristics of heart rate and blood pressure variability in primary aldosteronism. Am J Hypertens 1995, 8:479–486.
Spinelli L, Petretta M, Marciano F, et al.: Cardiac autonomic responses to volume overload in normal subjects and in patients with dilated cardiomyopathy. Am J Physiol 1999, 277:H1361–H1368.
Strehlow K, Nickenig G, Roeling J, et al.: AT1 receptor regulation in salt-sensitive hypertension. Am J Physiol 1999, 277:H1701–H1707.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tikhonoff, V., Kuznetsova, T., Stolarz-Skrzypek, K. et al. Modulation of genetic cardiovascular risk by age and lifestyle. Curr Cardio Risk Rep 2, 398–404 (2008). https://doi.org/10.1007/s12170-008-0070-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12170-008-0070-8