title: Associations of hypertension and its complications with variations in the xanthine dehydrogenase gene.
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.
authors: Division of Hypertension and Nephrology, National Cardiovascular Center, Suita, Japan.
authors: Jin
authors: J
authors: Yang
authors: Kei
authors: K
authors: Kamide
authors: Yoshihiro
authors: Y
authors: Kokubo
authors: Shin
authors: S
authors: Takiuchi
authors: Takeshi
authors: T
authors: Horio
authors: Tetsutaro
authors: T
authors: Matayoshi
authors: Hisayo
authors: H
authors: Yasuda
authors: Yoshikazu
authors: Y
authors: Miwa
authors: Masayoshi
authors: M
authors: Yoshii
authors: Fumiki
authors: F
authors: Yoshihara
authors: Satoko
authors: S
authors: Nakamura
authors: Hajime
authors: H
authors: Nakahama
authors: Hitonobu
authors: H
authors: Tomoike
authors: Toshiyuki
authors: T
authors: Miyata
authors: Yuhei
authors: Y
authors: Kawano
mesh_terms: D000368:Aged; D044466:Asian People / Q000235:genetics; D002340:Carotid Artery Diseases / Q000208:ethnology / Q000235:genetics*; D002908:Chronic Disease; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000208:ethnology / Q000235:genetics*; D007564:Japan; D007674:Kidney Diseases / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014968:Xanthine Dehydrogenase / Q000235:genetics*
chemical_list: D014968:Xanthine Dehydrogenase