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Genetic Control of Immune Variation across the Human Population
Author(s) -
Hacohen Nir
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.369.2
Subject(s) - biology , innate immune system , genetics , genetic variation , gene , genome wide association study , immune system , allele , single nucleotide polymorphism , genotype
A focus of our work is to develop systems‐level approaches to dissect the innate immune response to pathogens in dendritic cells, focusing on the pathway from receptor engagement to gene expression. An important dimension that is not well understood is the impact of inter‐individual genetic variation on pathogen responses, especially in the context of common diseases. Using a combination of experimental and computational approaches, we determined the quantitative effects of genetic variation on gene expression in response to viruses and bacterial ligands in human dendritic cells. We identified thousands of common cis genetic variants associated with gene expression after stimulation with E. coli lipopolysaccharide, influenza or IFNβ. We used promoter reporter assays and genome editing to localize and validate causal variants to binding sites of pathogen‐activated STAT and IRF transcription factors. We also identified a variant in IRF7 that is associated in trans with the type I interferon response to influenza virus. Many of the cis and trans variants are also known disease variants, suggesting how DC innate sensing may contribute to immune‐related diseases. Finally, we identified a class of genetic variants that affect splicing, cluster near known splice sites and overlap with GWAS loci at the same frequency as variants that affect expression. Our results reveal common alleles that explain inter‐individual variation in pathogen sensing and impact susceptibility to immune‐mediated diseases.