The effect of altitude on the expression of immune-related genes in Peruvian rural indigenous
Authors: Jaramillo-Valverde Luis , de Araújo Gilderlanio Santana , Poterico Julio A. , Martinez-Jaramillo Catalina , Roa-Linares Vicky , Alvites-Arrieta Sandra , Pablo-Ramirez Nelis , Ubillus Milward , Palma-Lozano Diana , Silva-Carvalho Carolina , Vasconcelos-da-Gama Luca , Costa Lucas F , Tarazona-Santos Eduardo , Raychaudhuri Soumya , Guio Heinner 
Published: March 2024

ABSTRACTBackground: Some genes associated with immune response have been elucidated in some Andean populations, which may explain part of the immune system adaptation and pathogen response in high-altitude residents. We performed differential expression analysis and mainly focused on genes with high fold-change between groups and those genes with differential expression related to the immune system. Methods: We performed a transcriptome analysis of Peruvian individuals, primarily from rural areas, with high genetic backgrounds from ancient indigenous people, exposed to different living altitudes (high vs low). We collected peripheral blood mononuclear cells (PBMC) from 62 volunteers and exposed them to bacterial lipopolysaccharide (LPS), Pam3CSK4 (a synthetic triacylated lipopeptide responsible for bacterial components), and R848 (an imidazoquinoline compound related to viral nucleic acids). Results: Differential expression analysis results and data integration analysis with immune system pathway data exhibit a set of 17 genes associated with the immune system, nine down-regulated genes (ITGAX, CCL22, CSF1, CXCL8, IL12A, MMP9, CSF2, PTGS2, ENSG00000138685.17), and eight up-regulated genes (HLA-DPB1, FN1, CD36, MMP2, HLA-DRB1, FCGR1A, CCL17, HLA-DRB5). These genes are notably enriched in antigen-presenting cells, such as dendritic cells and macrophages. Conclusion: The differential expression of immune system genes in native inhabitants with a prominent Andean genetic background highlights the active involvement of both the innate and adaptive immune systems. Remarkably, our study revealed a distinct gene expression signature in our population, setting it apart from other transcriptomic studies conducted thus far.AUTHOR SUMMARYLiving in high-altitude regions poses several environmental challenges for humans, including reduced oxygen levels, increased exposure to ultraviolet radiation, cold temperatures, and altered responses to pathogens, among other factors. Here we show genomic and transcriptome analyses of blood cells in Peruvian individuals, primarily from rural areas, from indigenous populations. We previously showed a robust adaptation signals related to altitude in Peruvian and Bolivian populations, identifying a significant association with the DUOX2 gene, which plays a crucial role in maintaining homeostasis in thyroid hormone production, as well as influencing the innate immune system and inflammatory response. We now find that differential expression analysis exhibits a set of 17 genes associated with the immune system, nine down-regulated genes (ITGAX, CCL22, CSF1, CXCL8, IL12A, MMP9, CSF2, PTGS2, ENSG00000138685.17), and eight up-regulated genes (HLA-DPB1, FN1, CD36, MMP2, HLA-DRB1, FCGR1A, CCL17, HLA-DRB5). These results suggest a distinct gene expression signature in our population, setting it apart from other transcriptomic studies conducted thus far.