Science

Abstract

Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-\uce\ub2 (IFN-\uce\ub2). We localized and validated causal variants to binding sites of pathogen-activated STAT (signal transducer and activator of transcription) and IRF (IFN-regulatory factor) transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I IFN induction in response to influenza infection. Our results reveal common alleles that explain interindividual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases.DP1 CA174427/CA/NCI NIH HHS/United StatesDP1 CA174427/CA/NCI NIH HHS/United StatesDP1 MH100706/DP/NCCDPHP CDC HHS/United StatesDP1 MH100706/MH/NIMH NIH HHS/United StatesDP2 OD002230/OD/NIH HHS/United StatesDP2 OD002230/OD/NIH HHS/United StatesF32 AG043267/AG/NIA NIH HHS/United StatesF32 AG043267/AG/NIA NIH HHS/United StatesP30 DK043351/DK/NIDDK NIH HHS/United StatesP50 HG006193/HG/NHGRI NIH HHS/United StatesP50 HG006193/HG/NHGRI NIH HHS/United StatesR01 AI091568/AI/NIAID NIH HHS/United StatesR01 AR063759/AR/NIAMS NIH HHS/United StatesR01 DK097768/DK/NIDDK NIH HHS/United StatesR01 HG004037/HG/NHGRI NIH HHS/United StatesR01 HG004037/HG/NHGRI NIH HHS/United StatesRC2 GM093080/GM/NIGMS NIH HHS/United StatesRC2 GM093080/GM/NIGMS NIH HHS/United StatesT32 GM007753/GM/NIGMS NIH HHS/United StatesT32 GM007753/GM/NIGMS NIH HHS/United StatesT32 HG002295/HG/NHGRI NIH HHS/United StatesT32 HG002295/HG/NHGRI NIH HHS/United StatesU19 AI082630/AI/NIAID NIH HHS/United StatesHoward Hughes Medical Institute/United States2014-09-07T00:00:00Z24604203PMC412474