Abstract
It has been reported that oxidative stress is involved in the pathophysiology of essential hypertension (EH), which is a multifactorial disorder. Extracellular superoxide dismutase (EC-SOD) protects the human body from oxidative stress by converting the toxic superoxide anion (O2−) into less toxic hydrogen peroxide (H2O2). In EC-SOD knockout mice, blood pressure was reported to be significantly higher than that seen in wild-type mice. The aim of this study was thus to investigate the relationship between EH and the human EC-SOD gene by using single-nucleotide polymorphisms (SNPs) in a haplotype-based case-control study. We selected 6 SNPs within the human EC-SOD gene (rs13306703, rs699473, rs699474, rs17881426, rs2536512 and rs1799895), and then performed case-control studies in 243 EH patients and 251 age-matched normotensive (NT) subjects. In Japanese subjects, no heterogeneity was found for rs699474, and no significant differences were observed between the EH and NT groups for the overall distribution of the genotypes or the alleles for each of the SNPs. However, in the haplotype-based case-control study that used rs13306703 and rs2536512, significant differences were observed in the overall distribution (x 2 = 14.26, p =0.003). The frequency of the T-A haplotype was significantly higher in the EH group than in the NT group (2.4% vs 0.0 %, p <0.001). Based on the results of our haplotype-based case-control study, the T-A haplotype may be a genetic marker for EH, and thus the EC-SOD gene might be a susceptibility gene for EH.
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Landis GN, Tower J : Superoxide dismutase evolution and life span regulation. Mech Ageing Dev 2005; 126: 365–379.
Fattman CL, Schaefer LM, Oury TD : Extracellular superoxide dismutase in biology and medicine. Free Radic Biol Med 2003; 35: 236–256.
Umemoto S, Tanaka M, Kawahara S, et al: Calcium antagonist reduces oxidative stress by upregulating Cu/Zn superoxide dismutase in stroke-prone spontaneously hypertensive rats. Hypertens Res 2004; 27: 877–885.
Tanaka M, Umemoto S, Kawahara S, et al: Angiotensin II type 1 receptor antagonist and angiotensin-converting enzyme inhibitor altered the activation of Cu/Zn-containing superoxide dismutase in the heart of stroke-prone spontaneously hypertensive rats. Hypertens Res 2005; 28: 67–77.
Afonso V, Champy R, Mitrovic D, Collin P, Lomri A : Reactive oxygen species and superoxide dismutases: role in joint diseases. Joint Bone Spine 2007; 74: 324–329.
Folz RJ, Guan J, Seldin MF, Oury TD, Enghild JJ, Crapo JD : Mouse extracellular superoxide dismutase: primary structure, tissue-specific gene expression, chromosomal localization, and lung in situ hybridization. Am J Respir Cell Mol Biol 1997; 17: 393–403.
Zhou L, Xiang W, Potts J, et al: Reduction in extracellular superoxide dismutase activity in African-American patients with hypertension. Free Radic Biol Med 2006; 41: 1384–1391.
Folz RJ, Crapo JD : Extracellular superoxide dismutase (SOD3) tissue-specific expression, genomic characterization, and computer-assisted sequence analysis of the human EC SOD gene. Genomics 1994; 22: 162–171.
Campo S, Sardo AM, Campo GM, et al: Extracellular superoxide dismutase (EC-SOD) gene mutations screening in a sample of Mediterranean population. Mutat Res 2005; 578: 143–148.
Son M, Cloyd CD, Rothstein JD, Rajendran B, Elliott JL : Aggregate formation in Cu, Zn superoxide dismutase related proteins. J Biol Chem 2003; 278: 14331–14336.
Strålin P, Karlsson K, Johansson BO, Marklund SL : The interstitium of the human arterial wall contains very large amounts of extracellular superoxide dismutase. Arterioscler Thromb Vasc Biol 1995; 15: 2032–2036.
Gongora MC, Qin Z, Laude K, et al: Role of extracellular superoxide dismutase in hypertension. Hypertension 2006; 48: 473–481.
Welch WJ, Chabrashvili T, Solis G, et al: Role of extracellular superoxide dismutase in the mouse angiotensin slow pressor response. Hypertension 2006; 48: 934–941.
Welch WJ, Blau J, Xie H, Chabrashvili T, Wilcox CS : Angiotensin-induced defects in renal oxygenation: role of oxidative stress. Am J Physiol Heart Circ Physiol 2005; 288: H22–H28.
Volpe M, Alderman MH, Furberg CD, et al: Beyond hypertension toward guidelines for cardiovascular risk reduction. Am J Hyperens 2004; 17: 1068–1074.
Dominiczak AF, Negrin DC, Clark JS, Brosnan MJ, McBride MW, Alexander MY : Genes and hypertension from gene mapping in experimental models to vascular gene transfer strategies. Hypertension 2000; 35: 164–172.
Aoi N, Soma M, Nakayama T, et al: Variable number of tandem repeat of the 5′-flanking region of type-C human natriuretic peptide receptor gene influences blood pressure levels in obesity-associated hypertension. Hypertens Res 2004; 27: 711–716.
Maruyama A, Nakayama T, Sato N, Mizutani Y, Furuya K, Yamamoto T : Association study using single nucleotide polymorphisms in the estrogen receptor β (ESR2) gene for preeclampsia. Hypertens Res 2004; 27: 903–909.
Livak KJ, Marmaro J, Todd JA : Towards fully automated genome-wide polymorphism screening. Nat Genet 1995; 9: 341–342.
Kobayashi Y, Nakayama T, Sato N, Izumi Y, Kokubun S, Soma M : Haplotype-based case-control study revealing an association between the adrenomedullin gene and proteinuria in subjects with essential hypertension. Hypertens Res 2005; 28: 229–236.
Morita A, Nakayama T, Doba N, Hinohara S, Soma M : Polymorphism of the C-reactive protein (CRP) gene is related to serum CRP level and arterial pulse wave velocity in healthy elderly Japanese. Hypertens Res 2006; 29: 323–331.
Hui P, Nakayama T, Morita A, et al: Common single nucleotide polymorphisms in Japanese patients with essential hypertension: aldehyde dehydrogenase 2 gene as a risk factor independent of alcohol consumption. Hypertens Res 2007; 30: 585–592.
Tamai M, Furuta H, Kawashima H, et al: Extracellular superoxide dismutase gene polymorphism is associated with insulin resistance and the susceptibility to type 2 diabetes. Diabetes Res Clin Pract 2006; 71: 140–145.
Chu Y, Alwahdani A, Iida S, Lund DD, Faraci FM, Heistad DD : Vascular effects of the human extracellular superoxide dimustase R213G variant. Circulation 2005; 112: 1047–1053.
Ozaki K, Ohnishi Y, Iida A, et al: Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 2002; 32: 650–654.
Zhang K, Calabrese P, Nordborg M, Sun F : Haplotype block structure and its applications to association studies: power and study designs. Am J Hum Genet 2002; 71: 1386–1394.
Morris RW, Kaplan NL : On the advantage of haplotype analysis in the presence of multiple disease susceptibility alleles. Genet Epidemiol 2002; 23: 221–233.
Sharma P, Hingorani A, Jia H, Hopper R, Brown MJ : Quantitative association between a newly identified molecular variant in the endothelin-2 gene and human essential hypertension. J Hypertens 1999; 9: 1281–1287.
Ombra MN, Forabosco P, Casula S, et al: Identification of a new candidate locus for uric acid nephrolithiasis. Am J Hum Genet 2001; 68: 1119–1129.
Morita A, Nakayama T, Soma M, Mizutani T : Association between the calcitonin-related peptide alpha (CALCA) gene and essential hypertension in Japanese subjects. Am J Hypertens 2007; 20: 527–532.
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Naganuma, T., Nakayama, T., Sato, N. et al. A Haplotype-Based Case-Control Study Examining Human Extracellular Superoxide Dismutase Gene and Essential Hypertension. Hypertens Res 31, 1533–1540 (2008). https://doi.org/10.1291/hypres.31.1533
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DOI: https://doi.org/10.1291/hypres.31.1533
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