Polymorphisms of the human IFNG gene noncoding regions

Interferon gamma (IFN-gamma) is a multifunctional cytokine that is essentia l in the development of Th1 cells and in cellular responses to a variety of intracellular pathogens including human immunodeficiency virus (HIV-1). We screened genomic DNA samples from a predominately Caucasian male populatio n of HIV-infected and healthy donors for polymorphisms in the human IFNG ge ne from -777 to +5608 by single-stranded conformational polymorphism. Surpr isingly, the proximal promoter (-777 to transcription start) is invariant a s no polymorphisms were found in over 100 samples tested. However, further screening revealed polymorphisms in other regions of the gene including a s ingle base insertion in a poly-T tract in the first intron, three single ba se pair substitutions in the third intron, and another single base pair sub stitution in the 3' untranslated region (UTR), Electrophoretic mobility shi ft assay was used to investigate whether these variants have altered DNA-bi nding abilities, since intronic enhancer elements have been reported for th e IFNG gene. Oligonucleotides constructed for two third intron variants sho wed no difference in DNA-binding abilities as compared with wild-type seque nces. However, the 3'UTR variant showed the formation of unique DNA-binding complexes to radiolabeled oligonucleotide probes as compared with the wild -type sequence. The influence of a CA-repeat microsatellite on AIDS disease progression in HIV-1 seroconverters was tested by a Cox proportional hazar ds model. There is no evidence of an association between alleles and infect ion with HIV-1 or progression to AIDS. We report an invariant proximal huma n IFNG promoter and the existence of multiple intronic variants and a poten tially functional 3'UTR polymorphism.