Genetic architecture of regulatory variation influencing response to human rhinovirus infection. M. Caliskan1, Y. Gilad1, C. Ober1,2 1) Human Gen, Univ Chicago, Chicago, IL; 2) Obstetrics and Gynecology, Univ Chicago, Chicago, IL.
Human rhinovirus (HRV) is the most prevalent human respiratory virus. Each year, HRV infects billions of people and is responsible for at least half of all common colds, the most common illness of human. In addition to common colds, HRV infection affects the morbidity of a range of respiratory illnesses, including bronchiolitis, pneumonia, asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Despite its biological importance, little is known about the genetic architecture of variation in response to HRV. To address this, we obtained genome wide genotype and gene expression data in paired peripheral blood mononuclear cell (PBMC) samples from 98 individuals; PBMCs were cultured for 24 hours with and without HRV. Among the 10,868 genes detected as expressed, 2,093 were significantly up-regulated and 3,464 were down-regulated in HRV-infected compared to uninfected PBMCs (Bonferroni corrected significance threshold). Among the genes differentially expressed, the top enriched canonical pathways included activation of IRF by cytosolic pattern recognition receptors, interferon signaling, role of RIGI-like receptors in antiviral innate immunity, and IL-12 signaling and production in macrophages. We next mapped local (cis) expression quantitative trait loci (eQTLs) in uninfected and HRV-infected PBMCs, and identified 590 genes with cis-eQTLs in uninfected and 530 genes with cis-eQTLs in HRV-infected PBMCs (FDR 1% threshold). More importantly, 32 genes had significantly different effects in untreated and treated cells, providing evidence for genotype x HRV interactions. These HRV-interacting regulatory variations were significantly enriched for lung function (FEV1/FVC ratio) GWAS P-values <0.10 in the Hutterites (Permutation P=0.0041), and pulmonary function genes reported in the NHGRI GWAS catalogue were enriched for genotype x HRV interaction P-values <0.10 (Permutation P=0.045). In summary, this study represents the first integrated genome-wide study of genetic variation and gene expression response to HRV infection and suggests that host genotypes that are associated with gene expression response to HRV have long-term and persistent effects on lung function phenotypes.
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