FCGR2A rs1801274 polymorphism is associated with response to natalizumab in multiple sclerosis patients

Multiple sclerosis (MS) is recognized as the most prevalent autoimmune disorder affecting the central nervous system (CNS). Natalizumab (NTZ) is among the commonly used high-efficacy treatments, showing efficacy in reducing MS activity and progression in majority of patients. NTZ acts by targeting alpha-4 integrin subunits on lymphocytes, crucial for facilitating leukocyte trafficking to sites of inflammation. Several factors can influence MS treatment success that can either be environmental or genetic. Currently, there are few established pharmacogenetic predictors of response to treatment in MS patients. One genetic variant associated with therapeutic response to monoclonal antibodies used in treatment is the single nucleotide polymorphism (SNP) rs1801274 in the FCGR2A gene. Therefore, the objective of this study is to assess whether this genetic variant can serve as a potential predictor of therapeutic failure in Natalizumab treatment for multiple sclerosis. A total of 104 blood samples were collected from patients admitted to two university hospitals in Rio de Janeiro, with approval from the ethics committee (CAAE:5,782,087). Genomic DNA was extracted from leukocytes for subsequent use in real-time PCR genotyping. Among the patients, 9 exhibited confirmed therapeutic failure to NTZ treatment. Following statistical analysis, a significant association was identified between the GG genotype of FCGR2A (p=0.0004, OR=0.3530) and therapeutic failure. Additionally, a higher frequency of the AG genotype was observed in patients who did not experience therapeutic failure (p=0.0002, OR=3.144). Previous research has posited that FCgRs may also impact the efficacy and tolerability of human monoclonal antibody strategies targeting anti-alpha-4 integrin. Given the genetic diversity of the Brazilian population due to miscegenation, our preliminary findings suggest the necessity to investigate the role of FCGR2A rs1801274 as a potential pharmacogenetic predictor for MS patients' response to NTZ.