Sex-specific effects of AQP4 gene polymorphisms on multiple sclerosis susceptibility and response to multidisciplinary rehabilitation

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects young adults with different clinical phenotypes: relapsing–remitting MS (RR-MS), secondary progressive MS (SP-MS), and primary progressive MS (PP-MS). Aquaporin 4 (AQP4), a protein found in astrocytes, plays a crucial role in CNS functions. We investigated the possible association of three AQP4 gene single-nucleotide polymorphisms (SNPs), rs2075575, rs162009, and rs335929, with MS risk and rehabilitation outcomes. SNPs were genotyped in 237 people with MS (pwMS), spanning all disease forms and enrolled in an intensive, multidisciplinary rehabilitation program, and 461 healthy controls (HCs). The AQP4 rs2075575 GG genotype was significantly less frequent in male pwRR-MS compared to HCs (15.4% vs. 29.1%, p = 0.033, OR = 0.44), suggesting a protective role. Haplotype analysis identified the rs2075575(A)-rs162009(A)-rs335929(C) (A-A-C) haplotype as an MS risk factor, particularly in males (p = 0.001, OR = 2.70). Finally, the rs335929 SNP was significantly associated with EDSS improvement after rehabilitation (p = 0.011), with the CC genotype showing the highest mean ΔEDSS in pwRR-MS (p = 0.009), especially in males (p = 0.003). AQP4 gene SNPs may influence both MS susceptibility and rehabilitation outcomes, with sex-specific effects. Further studies are needed to understand the mechanisms behind these associations and their potential for personalized treatment strategies in MS.