Functional Characterization of Genetic Polymorphisms Identified in the Promoter Region of the Xanthine Oxidase Gene

Abstract

Xanthine oxidase (XO) catalyzes the oxidation of endogenous and exogenous purines and pyrimidines. In the present study, we investigated polymorphisms in the promoter region of the XO gene. Sequence variations in the 5'-flanking region were screened using denaturing high-performance liquid chromatography (DHPLC) on DNA samples from 196 unrelated Japanese individuals. Thirteen polymorphisms were identified and 13 haplotypes were classified by haplotype analysis. The promoter activities of these polymorphisms were measured by luciferase assay in the human hepatoma cell lines HepG2 and Huh-7. Transcriptional activity was significantly lower in cell lines transfected with the reporter construct containing 5-kb upstream fragments with -1756T than in those with wild-type -1756C. Our results indicate that genetic variation in the promoter region of XO may determine interindividual differences in XO gene expression.

Polymorphism of Genes Involved in Purine Metabolism (XDH, AOX1, MOCOS) in Kidney Transplant Recipients Receiving Azathioprine

“…On the other hand, rs4407290 is a relatively rare variant, inherited by only 8 patients included in this study and 14 individuals from the article by Smith et al, 8 which might result in false negative, and false positive conclusions. Finally, in vitro studies suggest that promoter polymorphisms of XDH can also be responsible for an observed individual variability in enzyme activity 23 and though should be a subject to a future investigation in relation to thiopurine treatment safety and efficacy.…”

Inflammation: a possible mechanism for a causative role of hyperuricemia/gout in cardiovascular disease

“…In a recent study, genetic predisposition to MSUC-induced inflammation has been shown, as polymorphisms in Toll-like receptors were reported to be associated with the development of clinical manifestations of gout 9 . In addition, variants in xanthine oxidase have been observed to influence the activity of this enzyme 10 and have also been associated with an increased risk of hypertension in a study on about 2900 patients 11 . Taken together, these findings suggest a pathophysiological link between XO over-activity as a contributor to CV risk, but also have therapeutic implications as to whether to target urate, XO, inflammation or all of them in patients with urate deposition and vascular risk factors 2 .…”

The role of pharmacogenetics in nonmalignant gastrointestinal diseases

“…66–68 Several studies have identified genetic polymorphisms in the gene encoding xanthine oxidase 69 and its promoter region that might determine inter-individual differences in expression of this gene. 70 Xanthine oxidase levels are also reduced by allopurinol and methotrexate, which might increase the bioavailability of 6-MP and so potentially increase the efficacy (and risk of toxicity) of 6-MP.…”