Influence of FCGR2A (rs1801274) and FCGR3A (rs396991) polymorphisms on natalizumab response on multiple sclerosis

Genetic variants in Fc gamma receptors (FcγRs) have been implicated in the therapeutic failure of monoclonal antibodies. Natalizumab (NTZ), a monoclonal antibody widely used in the treatment of multiple sclerosis (MS), prevents immune cell migration into the central nervous system, thereby reducing inflammation and demyelination. Despite its high efficacy, a subset of patients does not respond to NTZ, with single nucleotide polymorphisms (SNPs) in FcγRs emerging as potential pharmacogenetic biomarkers.

In this study, we evaluated patients with relapsing-remitting MS diagnosed according to the McDonald criteria and treated with NTZ. Genotyping of FCGR2A (rs1801274) and FCGR3A (rs396991) was performed using TaqMan-PCR allelic discrimination. Cytokine levels were quantified using x-MAP technology.

Of the 116 patients analyzed, 13 were classified as non-responders. Logistic regression adjusted for sex and age revealed that the FCGR2A AG genotype was significantly associated with a reduced risk of therapeutic failure (OR = 0.044; p = 0.014), while for FCGR3A, the AC genotype was also associated with a protective effect (OR = 0.077; p = 0.025). No significant effects of age or sex were observed in either model. Receiver Operating Characteristic (ROC) analysis showed that the FCGR2A rs1801274 GG genotype had weak predictive value for therapeutic failure, whereas FCGR3A rs396991 AA had modest discriminatory power. Additionally, these genotypes were associated with reduced levels of specific pro-inflammatory cytokines.

The FCGR2A AG and FCGR3A AC genotypes were associated with a lower risk of NTZ treatment failure, suggesting that FcγR polymorphisms may serve as biomarkers for therapeutic response in MS.