Abstract
Myeloperoxidase (MPO) may play an important role not only in host defense reactions but also in local inflammations, especially in atherosclerotic diseases such as hypertensive nephrosclerosis (HN). Paradoxically, MPO-deficient mice have been reported to show increased atherosclerosis compared with wild mice, although higher MPO levels are thought to exacerbate atherosclerotic disease. To clarify the genetic role of MPO in HN, we examined the function and distribution of the −463G/A polymorphism located in the promoter region of the MPO gene with ex vivo flow cytometry analysis and a study in end-stage renal disease patients, respectively. This polymorphism has been reported to have a functional significance in vitro, with the A allele being associated with lower MPO expression. In the present study, we also found significantly higher reactive oxygen species (ROS) production with peripheral neutrophils isolated from subjects with the GG genotype compared with those from subjects with other genotypes by flow cytometry assay with 2-[6-(4′-amino) phenoxy-3H-xanthen-3-on-9-yl] benzoic acid (APF), which shows higher sensitivity with hypochlorite (OCl−). Genotyping the −463G/A polymorphism in HN, chronic glomerulonephritis (CGN) and diabetic nephropathy (DM) patients who were under hemodialysis treatment demonstrated that the GG genotype was more frequent in the HN group than in the CGN and DM groups. However, the distribution of the GG genotype in the HN group was similar to that in healthy individuals. Although the −463G/A polymorphism is associated with ROS production, careful interpretation may be required to conclude that the −463G/A polymorphism can serve as a useful marker of atherosclerosis and cardiovascular events in dialysis patients.
Similar content being viewed by others
Article PDF
References
Nicholls SJ, Hazen SL : Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005; 25: 1–9.
Zhang R, Brennan ML, Fu X, et al: Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 2001; 286: 2136–2142.
Brennan ML, Anderson MM, Shih DM, et al: Increased atherosclerosis in myeloperoxidase-deficient mice. J Clin Invest 2001; 107: 419–430.
Takizawa S, Aratani Y, Fukuyama N, et al: Deficiency of myeloperoxidase increases infarct volume and nitrotyrosine formation in mouse brain. J Cereb Blood Flow Metab 2002; 22: 50–54.
Austin GE, Lam L, Zaki SR, et al: Sequence comparison of putative regulatory DNA of the 5′ flanking region of the myeloperoxidase gene in normal and leukemic bone marrow cells. Leukemia 1993; 7: 1445–1450.
Piedrafita FJ, Molander RB, Vansant G, Orlova EA, Pfahl M, Reynolds WF : An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element. J Biol Chem 1996; 271: 14412–14420.
Reynolds WF, Chang E, Douer D, Ball ED, Kanda V : An allelic association implicates myeloperoxidase in the etiology of acute promyelocytic leukemia. Blood 1997; 90: 2730–2737.
Crawford FC, Freeman MJ, Schinka JA, et al: Association between Alzheimer's disease and a functional polymorphism in the myeloperoxidase gene. Exp Neurol 2001; 167: 456–459.
London SJ, Lehman TA, Taylor JA : Myeloperoxidase genetic polymorphism and lung cancer risk. Cancer Res 1997; 57: 5001–5003.
Asselbergs FW, Tervaert JW, Tio RA : Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2004; 350: 516–518.
Pecoits-Filho R, Stenvinkel P, Marchlewska A, et al: A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients. Kidney Int Suppl 2003; ( 84): S172–S176.
Nangaku M : Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 2006; 17: 17–25.
Kimura N, Yonemoto S, Machiguchi T, Li X, Kimura H, Yoshida H : Synthetic/secreting and apoptotic phenotypes in renal biopsy tissues from hypertensive nephrosclerosis patients. Hypertens Res 2006; 29: 573–580.
Doi K, Doi H, Noiri E, Nakao A, Fujita T, Tokunaga K : High-throughput single nucleotide polymorphism typing by fluorescent single-strand conformation polymorphism analysis with capillary electrophoresis. Electrophoresis 2004; 25: 833–838.
Usui C, Shibata N, Ohnuma T, et al: No genetic association between the myeloperoxidase gene −463 polymorphism and estrogen receptor-alpha gene polymorphisms and Japanese sporadic Alzheimer's disease. Dement Geriatr Cogn Disord 2006; 21: 296–299.
Matsuo K, Hamajima N, Suzuki R, et al: No substantial difference in genotype frequencies of interleukin and myeloperoxidase polymorphisms between malignant lymphoma patients and non-cancer controls. Haematologica 2001; 86: 602–608.
Katsuda N, Hamajima N, Tamakoshi A, et al: Helicobacter pylori seropositivity and the myeloperoxidase G−463A polymorphism in combination with interleukin-1B C−31T in Japanese health checkup examinees. Jpn J Clin Oncol 2003; 33: 192–197.
Setsukinai K, Urano Y, Kakinuma K, Maejima JH, Nagano T : Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species. J Biol Chem 2003; 278: 3170–3175.
Saran M, Beck-Speier I, Fellerhoff B, Bauer G : Phagocytic killing of microorganisms by radical processes: consequences of the reaction of hydroxyl radicals with chloride yielding chlorine atoms. Free Radic Biol Med 1999; 26: 482–490.
Candeias LP, Patel KB, Stratford MR, Wardman P : Free hydroxyl radicals are formed on reaction between the neutrophil-derived species superoxide anion and hypochlorous acid. FEBS Lett 1993; 333: 151–153.
Zhang C, Yang J, Jacobs JD, Jennings LK : Interaction of myeloperoxidase with vascular NAD(P)H oxidase–derived reactive oxygen species in vasculature: implications for vascular diseases. Am J Physiol Heart Circ Physiol 2003; 285: H2563–H2572.
Clark RA, Klebanoff SJ : Chemotactic factor inactivation by the myeloperoxidase-hydrogen peroxide-halide system. J Clin Invest 1979; 64: 913–920.
el-Hag A, Clark RA : Immunosuppression by activated human neutrophils. Dependence on the myeloperoxidase system. J Immunol 1987; 139: 2406–2413.
McGrath MS, Kahn JO, Herndier BG : Development of WF10, a novel macrophage-regulating agent. Curr Opin Investig Drugs 2002; 3: 365–573.
Kemp E, Dieperink H, Horn T, et al: WF10 in xenotransplantation—a potential new approach. Transplant Proc 2000; 32: 1018–1019.
Anders HJ, Vielhauer V, Schlondorff D : Chemokines and chemokine receptors are involved in the resolution or progression of renal disease. Kidney Int 2003; 63: 401–415.
Ohashi J, Yamamoto S, Tsuchiya N, et al: Comparison of statistical power between 2 * 2 allele frequency and allele positivity tables in case-control studies of complex disease genes. Ann Hum Genet 2001; 65: 197–206.
Iseki K, Ikemiya Y, Iseki C, Takishita S : Proteinuria and the risk of developing end-stage renal disease. Kidney Int 2003; 63: 1468–1474.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Doi, K., Noiri, E., Maeda, R. et al. Functional Polymorphism of the Myeloperoxidase Gene in Hypertensive Nephrosclerosis Dialysis Patients. Hypertens Res 30, 1193–1198 (2007). https://doi.org/10.1291/hypres.30.1193
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.30.1193
Keywords
This article is cited by
-
Genetic polymorphisms associated with reactive oxygen species and blood pressure regulation
The Pharmacogenomics Journal (2019)
-
Comparative Transcriptomic Analyses by RNA-seq to Elucidate Differentially Expressed Genes in the Muscle of Korean Thoroughbred Horses
Applied Biochemistry and Biotechnology (2016)
-
Polymorphisms in the myeloperoxidase gene locus are associated with acute kidney injury–related outcomes
Kidney International (2012)