Impacto de polimorfismos genéticos e resposta ao tratamento com natalizumabe em pacientes com esclerose múltipla

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with multifactorial etiology, in which genetic and environmental factors influence both the risk of development and the response to treatment. Natalizumab (NTZ), an anti-α4β1 integrin monoclonal antibody, represents an important therapeutic option for patients with the relapsing-remitting form of the disease, although the clinical response varies widely between individuals. In this context, pharmacogenetics emerges as a promising tool for personalizing treatment, allowing the identification of biomarkers predictive of therapeutic response. The main objective of this study was to investigate the association between genetic polymorphisms in the FCGR2A, FCGR3A and VDR genes and the clinical response to NTZ in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). A total of 116 patients treated with NTZ at two referral centers were included and classified as responders (n=103) and non-responders (n=13) based on the annualized relapse rate (ART) and disability progression measured by the Expanded Disability Status Scale (EDSS). Genotyping was performed by real-time PCR using TaqMan® probes, and plasma quantification of inflammatory cytokines (IFN-γ, IL-4, IL-6, and IL-18) was conducted by multiplex immunofluorescence assay (xMAP®) to assess the immunological profile. Significant associations were observed between response to NTZ and the FCGR2A rs1801274 and FCGR3A rs396991 polymorphisms, with the AG and CA genotypes (respectively) being more frequent among responders, while GG (FCGR2A) and AA (FCGR3A) predominated in non-responders. Regarding the VDR gene, the CC genotype of rs7975232 was more prevalent among non-responders, whereas the AA genotype of rs731236 was exclusive to responders. The rs11568820 polymorphism showed a significant association with therapeutic response, regardless of genotype, unlike rs4516035, which did not demonstrate statistical significance. Despite the lack of correlation between VDR polymorphisms and plasma cytokine concentrations, the data suggest that variants in this gene may modulate the immune response indirectly, influencing treatment efficacy. Our data indicate that the FCGR2A rs1801274 and FCGR3A rs396991 polymorphisms have potential as pharmacogenetic biomarkers of response to NTZ in patients with multiple sclerosis. Although variants in the VDR gene demonstrate preliminary associations, additional functional studies are needed to elucidate their mechanisms. These outcomes highlight the relevance of pharmacogenetics in personalized medicine and contribute to the development of individualized therapeutic strategies in multiple sclerosis.