IRF5 Genetic Risk Haplotype Influences Host B Cell Gene Responses to Epstein-Barr Virus (EBV) (49.14)

Abstract Both gene and environment interactions play keyroles in the development of systemic lupus erythematosus (SLE). We examined effects of the IRF5 lupus risk haplotype upon the host’s B cell response to the binding or infection with EBV, a suspected environmental trigger for SLE. Whole genome microarray expression profile data was collected from cells exposed to EBV for 16 hours. Analysis of gene expression by gene set enrichment analysis revealed that key differences in expression between SLE patients and controls (or individuals carrying the IRF5 risk and non-risk haplotype) were in a subset of interferon response genes. Patients with the IRF5 risk haplotype have a heightened interferon signature under all experimental conditions; whereas, the patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of unrelated, matched controls. Overexpression of interferon pathway genes in B cells following viral exposure in control individuals carrying the IRF5 risk haplotype suggests that the IRF5 risk alleles alone can modulate ones biological response to the environmental insult. Patients carrying either the IRF5 risk or non-risk alleles appear to already be predisposed to having a higher interferon signature even without exposure to virus, suggesting that other genetic factors are also influencing the interferon response, independent of virus. Support by NIH (AI007633 and AI31584).