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 different databases (PubMed, Scopus, Web of Science, SciELO, and LILACS) up to September 2026 synthesized findings from genetic association studies, HLA typing, and genome-wide studies. Large patient cohorts mostly come from Southeast Asia, while cohorts from Africa and Latin America are small (≤ 150 patients). World Health Organization guidelines from 1997 and 1999 were the most frequent. Notably, specific HLA alleles—particularly HLA-A*24—along with MICB and PLCE1 gene variants show 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 several cohorts and epidemiological settings. Conversely, certain variants, such as FCγR2A R/R131, appear 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 global clinical use; nevertheless, large-scale genetic analyses have yielded novel insights that warrant further investigation in large, multi-ethnic studies integrating host and viral genomic data. Genetic analyses are crucial for vaccine efficacy studies and for identifying therapeutic targets to prevent dengue infection and reduce the risk of severe disease.