Association of AQP4 single nucleotide polymorphisms (rs335929 and rs2075575) with Parkinson's disease: A case-control study

Objective: The glymphatic system plays an important role in brain waste removal and is functionally and structurally dependent on astrocyte aquaporin-4 (AQP4). Genetic variation in the AQP4 gene has therefore been hypothesized to be associated with genetic susceptibility to neurodegenerative diseases. This study aimed to investigate whether two specific single nucleotide polymorphisms (SNP) in the AQP4 gene, rs335929, and rs2075575, are associated with the risk and clinical features of PD.

Methods: A total of 950 participants, including 475 patients with sporadic PD and 475 independent healthy controls, were included in this case-control study. Two SNPs (rs335929 and rs2075575) of the AQP4 gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Sanger sequencing was used to determine whether the genotyping results were accurate. A chi-square (χ2) test was used to compare the frequencies of alleles and genotypes between patients and controls. Logistic regression was used to calculate dominance ratios (OR) and 95% confidence intervals (CI).

Results: The difference between rs2075575 in the dominant model (GG vs GA + AA: P = 0.019) and the overdominant model (GG + AA vs GA: P = 0.013) was statistically significant. Subgroup analysis showed that the frequency of the rs2075575 A allele was significantly higher in female PD patients than in matched female controls (P = 0.017). rs2075575 A allele was significantly more frequent in LOPD patients than in matched elderly controls (P = 0.033). rs335929 polymorphism was not significantly correlated with PD susceptibility in either the overall or subgroup analysis. Haplotype analysis between the two SNPs did not show an association with PD susceptibility. In addition, we found that the rs2075575 G allele was significantly associated with Rapid Eye Movement Behaviour Disorder (RBD) (P = 0.044), and the rs335929 A allele with memory impairment (P = 0.028) in PD.

Conclusion: The AQP4 gene rs2075575 polymorphism may be associated with PD susceptibility, but not the rs335929 polymorphism. rs2075575 is associated with RBD and rs335929 is associated with memory cognition. Regulation of the glymphatic system by interfering with the genetics of AQP4 and thus influencing the pathology of PD may be a direction worth investigating. Studies in larger sample sizes and across ethnicities are essential for further understanding the potential association between AQP genes and PD pathogenesis.