The effect of altitude on the expression of immune-related genes in Peruvian rural indigenous

BackgroundGenetic factors influencing immune response pathways in Andean populations may underlie adaptations to high-altitude environments. To investigate transcriptomic signatures associated with altitude, we analyzed immune-related gene expression across individuals residing at different elevations. MethodsWe recruited 62 Peruvian volunteers, predominantly from rural regions with high proportions of indigenous ancestry, living at low and high altitudes. Peripheral blood mononuclear cells (PBMCs) were stimulated with bacterial lipopolysaccharide (LPS), Pam3CSK4 (a synthetic triacylated lipopeptide), and R848 (an imidazoquinoline analog of viral nucleic acids). Population structure and ancestry were characterized, and transcriptome-wide differential expression analyses were performed. ResultsWe identified 30 genes with significant altitude-associated expression differences, including 22 downregulated (e.g., FN1, CD36, FOS) and nine upregulated genes. Functional enrichment indicated roles in acute inflammatory response, leukocyte migration, and positive regulation of myeloid leukocyte differentiation. ConclusionsHigh- and low-altitude Andean individuals exhibit distinct immune gene expression profiles, defining a population-specific transcriptomic signature that may reflect altitude-related immune adaptation. AUTHOR SUMMARYAndean populations exhibit genetic adaptations in immune response pathways, potentially linked to high-altitude living. To investigate this, we conducted genome-wide and transcriptome-wide analyses to identify immune-related gene expression differences between high- and low-altitude residents. We analyzed the genetic structure and ancestry of Peruvian individuals (primarily rural, with strong indigenous ancestry) living at different altitudes. Peripheral blood mononuclear cells (PBMCs) from 62 volunteers were stimulated with bacterial (LPS, Pam3CSK4) and viral (R848) mimics to assess immune responses. Differential expression analysis identified 22 down-regulated genes (e.g., FN1, CD36, FOS) and nine up-regulated genes, enriched in acute inflammatory response, leukocyte migration, and myeloid leukocyte differentiation. Our findings reveal a unique immune gene expression profile in Andean highlanders, distinct from other populations, suggesting adaptive modulation of both innate and adaptive immunity in response to high-altitude challenges.