A haplotype-based case-control study examining human extracellular superoxide dismutase gene and essential hypertension

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. SIMILAR CONTENT BEING VIEWED BY OTHERS POLYMORPHISMS OF THE MATRIX METALLOPROTEINASE GENES ARE ASSOCIATED WITH

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Article 16 February 2023 ARTICLE PDF REFERENCES * Landis GN, Tower J : Superoxide dismutase evolution and life span regulation. _Mech Ageing Dev_ 2005; 126: 365–379. Article  CAS  PubMed 

Google Scholar  * Fattman CL, Schaefer LM, Oury TD : Extracellular superoxide dismutase in biology and medicine. _Free Radic Biol Med_ 2003; 35: 236–256. Article  CAS  PubMed  Google Scholar

  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS 

PubMed  Google Scholar  * 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.

Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar

  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  PubMed  Google Scholar  * Gongora MC,

Qin Z, Laude K, _et al_: Role of extracellular superoxide dismutase in hypertension. _Hypertension_ 2006; 48: 473–481. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS

  PubMed  Google Scholar  * Volpe M, Alderman MH, Furberg CD, _et al_: Beyond hypertension toward guidelines for cardiovascular risk reduction. _Am J Hyperens_ 2004; 17: 1068–1074. Google

Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * Livak KJ, Marmaro J, Todd JA : Towards fully automated genome-wide polymorphism screening. _Nat Genet_ 1995; 9: 341–342. Article  CAS 

PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS

  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar

  * 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. Article 

CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * Morris RW, Kaplan NL : On the advantage of haplotype analysis in the presence of

multiple disease susceptibility alleles. _Genet Epidemiol_ 2002; 23: 221–233. Article  PubMed  Google Scholar  * 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. Article  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Division of Molecular Diagnostics, Department Advanced Medical Science, Nihon

University School of Medicine, Tokyo, Japan Takahiro Naganuma, Tomohiro Nakayama, Naoyuki Sato, Zhenyan Fu & Noriko Aoi * Department of Biological Applied Chemistry, Toyo University

Graduate School of Engineering, Saitama, Japan Takahiro Naganuma & Ron Usami * Department of Cardiovascular Medicine, First Affiliated Hospital, Xinjiang Medical University, Urumqi, P.R.

China Zhenyan Fu * Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan Masayoshi Soma Authors * Takahiro Naganuma View author

publications You can also search for this author inPubMed Google Scholar * Tomohiro Nakayama View author publications You can also search for this author inPubMed Google Scholar * Naoyuki

Sato View author publications You can also search for this author inPubMed Google Scholar * Zhenyan Fu View author publications You can also search for this author inPubMed Google Scholar *

Masayoshi Soma View author publications You can also search for this author inPubMed Google Scholar * Noriko Aoi View author publications You can also search for this author inPubMed Google

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Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 17 December 2007 * Accepted: 27 April

2008 * Issue Date: 01 August 2008 * DOI: https://doi.org/10.1291/hypres.31.1533 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable

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hypertension * extracellular superoxide dismutase * single-nucleotide polymorphism * haplotype * case-control study