The genetics of Dengue immunity: Identifying key factors for disease outcomes and implications for personalized prevention and treatment

Background: Dengue virus (DENV) infection triggers a wide spectrum of clinical outcomes, from mild febrile illness to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). While environmental and virological factors contribute to disease severity, host genetic variability plays a crucial role in modulating immune responses. This review explores the genetic determinants influencing dengue outcomes, focusing on polymorphisms in cytokine genes, human leukocyte antigen (HLA) alleles, and FcγR variants. These genetic factors impact innate and adaptive immunity, shaping infants and the elderly to be generally more susceptible to severe manifestations, possibly due to underdeveloped or waning immune responses the balance between protective responses and immunopathology, such as antibody-dependent enhancement (ADE). We also reviewed how prior infections and host immunogenetics interact to influence cross-immunity and disease risk. Advances in genomics and systems biology have enabled the identification of risk-associated alleles and potential biomarkers for disease stratification. Personalized medicine approaches, including genetic risk profiling, targeted therapies, and genotype-informed vaccine strategies, hold promise for improving dengue prevention and treatment. However, challenges remain in implementing these strategies in low-resource settings. Expanding genomic studies across diverse populations and integrating multi-omics data are essential for translating genetic insights into clinical practice. Ultimately, understanding the genetic basis of dengue immunity could revolutionize public health interventions in endemic regions.