Influence of Apolipoprotein E polymorphism on susceptibility of Wilson disease

Abstract

Wilson disease (WD) is an autosomal-recessive disorder caused by mutations in the ATP7B gene leading to abnormal copper deposition in liver and brain. WD manifests diverse neurological and hepatic phenotypes and different age of onset, even among the siblings, with same mutational background suggesting complex nature of the disease and involvement of other candidate genes. In that context, Apolipoprotein E (APOE) and Prion Protein (PRNP) have been proposed to be potential candidates for modifying the WD phenotype and age of onset. This study aims to identify the contribution of APOE and PRNP polymorphisms on the variable phenotypic expression of Indian WD patients. A total of 171 WD patients and 291 controls from Indian population were included in this study. Two APOE cSNPs (rs429358 and rs7412) resulting in three isoforms and M129V (rs1799990) polymorphism of PRNP were examined for their association with WD and its clinical phenotypes. The APOE ԑ4 allele was found to be significantly overrepresented in WD patients compared to controls. However, the frequency of the APOE ԑ3 allele and ԑ3/ԑ3 genotype was significantly higher in WD patients without cognitive behavior impairment compared to the ones with the impairment. On the contrary, the PRNP allele representing Val129 was found to be present in higher proportion in WD patients with cognitive behavioral decline. Our data suggest that the APOE ԑ4 allele could act as a potential risk for the pathogenesis of WD. Also, APOE and PRNP might contribute toward the cognitive behavioral decline in a section of WD patients.

Potential Role of Brain-Derived Neurotrophic Factor and Dopamine Receptor D2 Gene Variants as Modifiers for the Susceptibility and Clinical Course of Wilson’s Disease

“…Even, the mean age does not vary significantly between the groups bearing different genotype of this polymorphism. This result is similar to our previous finding, where APOE variants showed an overall association with the disease (Roy et al, 2017). Besides, other studies have also reported the association of DMT1 variant with the susceptibility of the disease (Przybyłkowski et al, 2014).…”

“…Interestingly, a Copper metabolism MURR1 domain containing protein 1 (COMMD1) mutation has been associated with abnormally high urinary copper in one patient (Gupta et al, 2010). Again, we have found association of APOE and PRNP polymorphisms as modifiers of susceptibility and clinical features among Indian WD patients (Roy et al, 2017). However, all the variable clinical features of WD cannot be explained on the basis of these genes.…”

Dopamine β hydroxylase (DBH) polymorphisms do not contribute towards the clinical course of Wilson's disease in Indian patients

“…In vivo and cell‐based experiments have revealed that transcription of DBH may be induced by estradiol, which prompted us to investigate the distribution of allele and genotype frequencies of DBH polymorphisms among the male and female WD patients present with neurological symptoms (see Supporting information, Table S3). We did not observe any sex‐specific preponderance of any allele or genotype of the selected DBH polymorphisms.…”

Wilson’s disease: update on pathogenesis, biomarkers and treatments

“…14 Roy et al subsequently suggested that APOE and PRNP genotypes may be associated with cognitive or behavioural symptoms. 15 A whole-exome sequencing study examining genes in the ATP7B interactome suggested rare variants in ESD and INO80 might also affect phenotype. 10…”