Apolipoprotein E gene (APOE) genotype in Wilson's disease: impact on clinical presentation

Wilson's disease (WD), an inherited copper metabolism disorder that leads to pathological tissue copper accumulation and secondary organ damage, is caused by mutations in the ATP-ase 7B gene (ATP7B). The apolipoprotein E gene (APOE) alleles ε2, ε3, and ε4 produce three different apoE isoforms with different biological effects, which can determine risks of many human diseases, including neurodegenerative and liver disease. This study aimed to evaluate the impact of APOE genotype on the variability of WD phenotypic expression.

We analyzed data on 383 WD consecutive patients in the WD registry. The APOE genotypes (APOE ε3/ε3 (wild-type), APOE ε2-positive, and APOE ε4-positive) were determined and the APOE genotype effect on the phenotypic WD presentation was assessed in all symptomatic WD patients, as well as in patient subgroups divided according to sex and ATP7B genotype.

APOE genotype had no impact on WD presentation in the general population of symptomatic patients. However, APOE ε4-positive women tended to present WD symptoms earlier than women possessing the wild-type APOE ε3/ε3 genotype (24.2 vs. 27.9 years; p = 0.08). The effect of the APOE ε4-positive genotype was more pronounced in ATP7B p.H1069Q homozygous women, in whom disease symptoms started almost 6 years earlier (23.6 vs. 29.9 years; p < 0.05) than in APOE ε3/ε3 women.

In women, APOE ε4-positive genotype is associated with earlier onset of WD symptoms, particularly among ATP7B p.H1069Q homozygous patients. Further studies are needed to understand the mechanisms of these gender-dependent phenotypic effects.