A single nucleotide polymorphism in the first intron of the human IFN-γ gene:

Abstract

We have described previously a variable length CA repeat sequence in the first intron of the human IFN-γ gene and showed that allele #2 is associated with high in vitro IFN-γ production. In a consecutive study, allele #2 was found to be associated with allograft fibrosis in lung transplant patients, confirming its role as a marker of high IFN-γ production, both in vivo and in vitro. In this study we have sequenced 50 PCR products that had been typed previously by PAGE for the identification of CA microsatellite alleles. We report on a novel single nucleotide polymorphism, T to A, at the 5′ end of the CA repeat region in the first intron of the human IFN-γ gene (+874∗T/A). There is an absolute correlation between the presence of T allele and the presence of the high-producing microsatellite allele #2. This T to A polymorphism coincides with a putative NF-κB binding site which might have functional consequences for the transcription of the human IFN-γ gene. Therefore, the T to A polymorphism could directly influence the level of IFN-γ production associated with the CA microsatellite marker.

Introduction

It has been shown previously that a CA repeat microsatellite sequence in the first intron of the human interferon-γ (IFN-γ) gene is polymorphic 1, 2, 3. Our group has described five alleles of this microsatellite in the UK population, which differ by the number of CA repeats. Sequence analysis has shown that allele #1 corresponds to 11 CA repeats, allele #2 corresponds to 12 repeats, and alleles #3–#5 have 13–15 repeats, respectively. In a parallel study we have shown that high IFN-γ production, defined by the response to in vitro Con A stimulation of peripheral blood leukocytes followed by ELISA, correlates with the presence of allele #2 [3]. Individuals homozygous for allele #2 were shown to produce significantly more IFN-γ (p = 0.01) than individuals with other allele combinations. Here we report on a novel single nucleotide polymorphism at the 5′ end of the CA repeat region that correlates with the presence or absence of the high-producing allele #2. We speculate that this polymorphic site may affect IFN-γ gene expression as it coincides with a putative NF-κB binding site.