Genetic Insights from Whole Exome Sequencing on IL-6 Signaling Genes in NMOSD: Unraveling Potential Mechanisms of Inflammation and Treatment Outcomes Driven by Anti-AQP4 Status and Ethnical backgrounds
Elielson Veloso da Silva1, Renan Amphilophio Fernandes3, Jessica Vasques Raposo Vedovi1, Larissa Araujo Duarte3, Andreza Salvio Lemos2, Helena França Alcaraz Ferreira3, Anna Beatriz Scherer Vanzan1, Elisa Gouvea Gutman3, Karla Pinto Coelho Fadel2, Valéria Coelho Santa Rita Pereira4, Soniza Vieira Alves-Leon5
1Biomedical Science Institute, Laboratory of Translational Neurocience, UNIRIO, 2Laboratory of Translational Neurocience, UNIRIO, 3Biomedical Science Institute, Laboratory of Translational Neuroscience, UNIRIO and Clementino Fraga Filho University Hospital, UFRJ, Brazil., 4Clementino Fraga Filho University Hospital, UFRJ, Brazil., 5Biomedical Science Institute, Laboratory of Translational Neurocience, UNIRIO, Brazil and Clementino Fraga Filho University Hospital,UFRJ, Brazil.
Objective:
To identify potential genetic modulators of IL-6 signaling within a serodiverse anti-AQP4 NMOSD cohort and examine the distribution of significant genetic variants across different ethnic backgrounds and their predicted effects on gene expression.
Background:
IL-6 signaling is a key pathway in the pathophysiology of NMOSD. Genetic factors influencing IL-6-related genes may explain variations in disease mechanisms and treatment responses among anti-AQP4 serogroups. Additionally, ethnic background appears to influence disease susceptibility. However, no studies have explored these aspects in this rare autoimmune disease.
Design/Methods:
Genetic variants from whole-exome sequencing of 29 anti-AQP4 (+) and 11 anti-AQP4 (-) NMOSD patients were screened within IL-6 signaling genes across both serogroups. Population databases were utilized for variant frequency analysis. In silico predictions of gene expression effects were performed using eQTL databases and relevant literature.
Results:
The variant rs2228044 in IL6ST is associated with the seropositive group and linked to lower sgp130 levels, suggesting a potential role in disease mechanisms that warrants further investigation. Variants rs3810194 and rs2878342 in FCGRT are predicted to reduce gene expression, potentially impacting the recycling rate of the anti-IL6 monoclonal antibody, Satralizumab. According to the dbSNP database, all three variants are more frequently found in populations of African ancestry.
Conclusions:
The variant rs2228044 in IL6ST has been associated with lower sgp130 levels, an inhibitor of IL-6 trans-signaling, potentially contributing to a heightened basal inflammatory state in the anti-AQP4 seropositive group. This role in inflammation warrants further study to understand its impact on disease progression. Additionally, variants rs3810194 and rs2878342 in FCGRT may reduce its gene expression, affecting the recycling rate and efficacy of Satralizumab in the seronegative group. Notably, these variants are more frequent in individuals of African ancestry. Further investigation is needed into the clinical implications of these variants on NMOSD pathophysiology and treatment outcomes.
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