Abstract
Hyperuricemia and oxidative stress participate in the pathophysiology of hypertension and its complications. Xanthine dehydrogenase (XDH) produces urate and, in its oxidase isoform, reactive oxygen species. Here we have studied whether or not the genetic variations in XDH could be implicated in hypertension and its complications. By sequencing the promoter region and all exons of XDH in 48 subjects, we identified three missense mutations (G172R, A932T, N1109T) in a heterozygous state in addition to 34 variations, including 15 common single nucleotide polymorphisms (SNPs). The three missense mutations and eight common SNPs (11488C>G, 37387A>G, 44408A>G, 46774G>A, 47686C>T, 49245A>T, 66292C>G, and 69901A>C) were genotyped in 953 hypertensive Japanese subjects and in 1,818 subjects from a general Japanese population. Four hypertensive patients with rare missense mutations (G172R or N1109T) in homozygous form had severe hypertension. Multivariate logistic regression analysis showed a significant association of three SNPs with hypertension in men: 47686C>T (exon 22, odds ratio [OR]: 1.52, p=0.047) and 69901A>C (intron 31, OR: 3.14, p=0.039) in the recessive model, and 67873A>C (N1109T) (exon 31, OR: 1.84, p=0.018) in the dominant model. After full adjustment for all confounding factors, only one polymorphism (69901A>C) was found to be associated with carotid atherosclerosis in the dominant model (p=0.028). Multiple logistic regression analysis showed that one SNP (66292C>G) was significantly associated with chronic kidney disease (CKD: estimated creatinine clearance <60 mL/min) in the recessive model (p=0.0006). Our results suggest that genetic variations in XDH contribute partly to hypertension and its complications, including atherosclerosis and CKD.
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Rutherford PA : Genetic influences in human hypertension. J Hypertens 2003; 21: 19–22.
Andersson OK, Almgren T, Persson B, et al: Survival in treated hypertension: follow up study after two decades. BMJ 1998; 317: 167–171.
Halushka MK, Fan JB, Bentley K, et al: Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 1999; 22: 239–247.
Smithies O, Maeda N : Gene targeting approaches to complex genetic diseases: atherosclerosis and essential hypertension. Proc Natl Acad Sci U S A 1995; 92: 5266–5272.
Berry CE, Hare JM : Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol 2004; 555: 589–606.
Johnson RJ, Feig DI, Herrera-Acosta J, et al: Resurrection of uric acid as a causal risk factor in essential hypertension. Hypertension 2005; 45: 18–20.
Niskanen LK, Laaksonen DE, Nyyssonen K, et al: Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med 2004; 164: 1546–1551.
Freedman DS, Williamson DF, Gunter EW, et al: Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 1995; 141: 637–644.
Bengtsson C, Lapidus L, Stendahl C, et al: Hyperuricaemia and risk of cardiovascular disease and overall death. A 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. Acta Med Scand 1988; 224: 549–555.
Klein R, Klein BE, Cornoni JC, et al: Serum uric acid. Its relationship to coronary heart disease risk factors and cardiovascular disease, Evans County, Georgia. Arch Intern Med 1973; 132: 401–410.
Verdecchia P, Schillaci G, Reboldi G, et al: Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension 2000; 36: 1072–1078.
Alderman MH, Cohen H, Madhavan S, et al: Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 1999; 34: 144–150.
Iseki K, Oshiro S, Tozawa M, et al: Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res 2001; 24: 691–697.
Tomita M, Mizuno S, Yamanaka H, et al: Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers. J Epidemiol 2000; 10: 403–409.
Yu TF, Berger L, Dorph DJ, et al: Renal function in gout. V. Factors influencing the renal hemodynamics. Am J Med 1979; 67: 766–771.
Cai H, Harrison DG : Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000; 87: 840–844.
Chabrashvili T, Tojo A, Onozato ML, et al: Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney. Hypertension 2002; 39: 269–274.
Beswick RA, Zhang H, Marable D, et al: Long-term antioxidant administration attenuates mineralocorticoid hypertension and renal inflammatory response. Hypertension 2001; 37: 781–786.
Nishiyama A, Kobori H, Fukui T, et al: Role of angiotensin II and reactive oxygen species in cyclosporine A−dependent hypertension. Hypertension 2003; 42: 754–760.
Meng S, Cason GW, Gannon AW, et al: Oxidative stress in Dahl salt-sensitive hypertension. Hypertension 2003; 41: 1346–1352.
Wallwork CJ, Parks DA, Schmid-Schonbein GW : Xanthine oxidase activity in the dexamethasone-induced hypertensive rat. Microvasc Res 2003; 66: 30–37.
Laakso J, Mervaala E, Himberg JJ, et al: Increased kidney xanthine oxidoreductase activity in salt-induced experimental hypertension. Hypertension 1998; 32: 902–906.
Laakso JT, Teravainen TL, Martelin E, et al: Renal xanthine oxidoreductase activity during development of hypertension in spontaneously hypertensive rats. J Hypertens 2004; 22: 1333–1340.
Landmesser U, Spiekermann S, Dikalov S, et al: Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation 2002; 106: 3073–3078.
Lenda DM, Boegehold MA : Effect of a high-salt diet on oxidant enzyme activity in skeletal muscle microcirculation. Am J Physiol Heart Circ Physiol 2002; 282: H395–H402.
Ulker S, McMaster D, McKeown PP, et al: Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation. Cardiovasc Res 2003; 59: 488–500.
Minoshima S, Wang Y, Ichida K, et al: Mapping of the gene for human xanthine dehydrogenase (oxidase) (XDH) to band p23 of chromosome 2. Cytogenet Cell Genet 1995; 68: 52–53.
Kamide K, Takiuchi S, Tanaka C, et al: Three novel missense mutations of WNK4, a kinase mutated in inherited hypertension, in Japanese hypertensives: implication of clinical phenotypes. Am J Hypertens 2004; 17: 446–449.
Kamide K, Tanaka C, Takiuchi S, et al: Six missense mutations of the epithelial sodium channel β and γ subunits in Japanese hypertensives. Hypertens Res 2004; 27: 333–338.
Miwa Y, Takiuchi S, Kamide K, et al: Insertion/deletion polymorphism in clusterin gene influences serum lipid levels and carotid intima-media thickness in hypertensive Japanese females. Biochem Biophys Res Commun 2005; 331: 1587–1593.
Takiuchi S, Mannami T, Miyata T, et al: Identification of 21 single nucleotide polymorphisms in human hepatocyte growth factor gene and association with blood pressure and carotid atherosclerosis in the Japanese population. Atherosclerosis 2004; 173: 301–307.
Yasuda H, Kamide K, Takiuchi S, et al: Association of single nucleotide polymorphisms in endothelin family genes with the progression of atherosclerosis in patients with essential hypertension. J Hum Hypertens 2007; 21: 883–892.
Cockcroft DW, Gault MH : Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.
National Kidney Foundation : K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1–S266.
Tanaka C, Kamide K, Takiuchi S, et al: An alternative fast and convenient genotyping method for the screening of angiotensin converting enzyme gene polymorphisms. Hypertens Res 2003; 26: 301–306.
Okuda T, Fujioka Y, Kamide K, et al: Verification of 525 coding SNPs in 179 hypertension candidate genes in the Japanese population: identification of 159 SNPs in 93 genes. J Hum Genet 2002; 47: 387–394.
Mannami T, Baba S, Ogata J : Potential of carotid enlargement as a useful indicator affected by high blood pressure in a large general population of a Japanese city: the Suita study. Stroke 2000; 31: 2958–2965.
Eriksen BO, Ingebretsen OC : The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age. Kidney Int 2006; 69: 375–382.
Gelber RP, Kurth T, Kausz AT, et al: Association between body mass index and CKD in apparently healthy men. Am J Kidney Dis 2005; 46: 871–880.
Agarwal R, Andersen MJ : Prognostic importance of clinic and home blood pressure recordings in patients with chronic kidney disease. Kidney Int 2006; 69: 406–411.
Iseki K : Factors influencing the development of end-stage renal disease. Clin Exp Nephrol 2005; 9: 5–14.
Li H, Samouilov A, Liu X, et al: Characterization of the magnitude and kinetics of xanthine oxidase−catalyzed nitrate reduction: evaluation of its role in nitrite and nitric oxide generation in anoxic tissues. Biochemistry 2003; 42: 1150–1159.
Zhang Z, Blake DR, Stevens CR, et al: A reappraisal of xanthine dehydrogenase and oxidase in hypoxic reperfusion injury: the role of NADH as an electron donor. Free Radic Res 1998; 28: 151–164.
Xu P, Huecksteadt TP, Harrison R, et al: Molecular cloning, tissue expression of human xanthine dehydrogenase. Biochem Biophys Res Commun 1994; 199: 998–1004.
Angius A, Petretto E, Maestrale GB, et al: A new essential hypertension susceptibility locus on chromosome 2p24−p25, detected by genomewide search. Am J Hum Genet 2002; 71: 893–905.
Krushkal J, Ferrell R, Mockrin SC, et al: Genome-wide linkage analyses of systolic blood pressure using highly discordant siblings. Circulation 1999; 99: 1407–1410.
Rice T, Rankinen T, Province MA, et al: Genome-wide linkage analysis of systolic and diastolic blood pressure: the Quebec Family Study. Circulation 2000; 102: 1956–1963.
Atwood LD, Samollow PB, Hixson JE, et al: Genome-wide linkage analysis of blood pressure in Mexican Americans. Genet Epidemiol 2001; 20: 373–382.
Kamide K, Kokubo Y, Yang J, et al: Hypertension susceptibility genes on chromosome 2p24−p25 in a general Japanese population. J Hypertens 2005; 23: 955–960.
Kokubo Y, Inamoto N, Tomoike H, et al: Association of genetic polymorphisms of sodium-calcium exchanger 1, NCX1, with hypertension in a Japanese general population. Hypertens Res 2004; 27: 697–702.
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Yang, J., Kamide, K., Kokubo, Y. et al. Associations of Hypertension and Its Complications with Variations in the Xanthine Dehydrogenase Gene. Hypertens Res 31, 931–940 (2008). https://doi.org/10.1291/hypres.31.931
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DOI: https://doi.org/10.1291/hypres.31.931
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