Host Genetics, Population Diversity, and Dengue Infection: An Unsolved Paradigm

This narrative review examines recent literature on human genetic variation and the clinical spectrum of dengue. A comprehensive search through September 2026 synthesized findings from genetic association studies, HLA typing, and genome-wide studies. The evidence is systematically categorized according to the World Health Organization clinical classification. The majority of available data derive from investigations conducted in Southeast Asia, with limited contributions from Africa and Latin America. Notably, specific HLA alleles—particularly HLA-A*24—as well as MICB and PLCE1 gene variants demonstrate the strongest associations with severe dengue; however, these associations vary by population and viral serotype. Other immune response genes, including CD209, FCGR2A, and TNF, have also been implicated, although their effects exhibit inconsistency across diverse cohorts and epidemiological settings. Conversely, the impact of certain variants, such as FCGR2A R/R131, appears to be modulated by population context, infecting serotype, and infection history. A major limitation of the existing body of research is the prevalence of small sample sizes, heterogeneity in case definitions across guidelines, and insufficient adjustment for genetic diversity. To date, no genetic marker has been validated for routine clinical use on a global scale; nevertheless, large-scale genetic analyses have yielded novel insights that warrant further investigation in large, multi-ethnic studies integrating both host and viral genomic data. Genetic analyses are crucial for improving vaccine efficacy and for identifying therapeutic targets to prevent dengue infection and reduce the risk of severe disease.