Gene variants encoding proteins involved in antioxidant defense system and the clinical expression of Wilson disease

Background & aims: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism resulting from pathogenic mutations of the ATP7B gene. The basis of phenotypic variability of the disease is not understood. The main mechanism of copper toxicity is probably related to generation of intracellular oxidative stress. To evaluate whether interindividual variability within genes encoding proteins involved in antioxidant defense system may modulate phenotypic expressions of WD.

Methods: Variability within genes encoding the cytosolic enzymes: glutathione peroxidase (GPX1 rs1050450) and manganese superoxide dismutase (SOD2 rs4880), and peroxisomal enzyme: catalase (CAT rs1001179) were analysed in 435 patients. Individual genotypes were tested for their relationship with phenotypic features of WD.

Results: GPX1 genotypes were not related to phenotypic manifestations of WD. Among males homozygocity for the SOD2 rs4880 T allele was related to earlier onset of WD. Patients homozygous for the CAT rs1001179 T allele characterized with later onset of WD [median (interquartile range) age: 29.0 (14.0) years vs. 22.0 (12.0) years, respectively, P < 0.004], later manifestation of hepatic symptoms [34.5 (14.0) years vs. 22.0 (12.0) years, P < 0.0009], and later presentation of neurological symptoms [37.0 (16.0) years vs. 28.0 (13.0) years, P < 0.03] than those having one or two C alleles.

Conclusion: Variability within the CAT gene may be an important modifier of the clinical course of WD. SOD2 genotype may influence WD phenotype among males. These observations indirectly confirm a role of oxidative stress in the pathogenesis of WD, as well as indirectly suggest that peroxisomes impairment may be involved in WD pathophysiology.