A single nucleotide polymorphism in the proximal IFN-gamma promoter alters control of gene transcription

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Abstract
Interferon-gamma (IFN-γ) is an important cytokine that regulates cellular immune responses to intracellular pathogens and neoplasia. Regulation of IFN-γ expression is stringently controlled at the transcriptional level. In this report we describe two novel single nucleotide polymorphisms (SNPs); one, at −179 in the promoter, occurs in 4% of African Americans. This SNP represents a guanidine to thymidine transition and creates a potential AP-1 binding element. Electrophoretic mobility shift analysis reveals a unique complex binding to an oligonucleotide containing the variant −179T but not to the −179G using nuclear extracts from human peripheral blood T cells. In reporter gene assays, T cell lines transfected with the variant −204(179T) IFN-γ promoter show a six to 13-fold induction of luciferase activity in response to TNF-α over the common −204(179G) construct. The −179T allele identified in the proximal IFN-γ promoter confers TNF-α inducibility and may prove important in human immune disorders and responsiveness to pathogens.