IDENTIFICATION OF 3 NEW SINGLE NUCLEOTIDE POLYMORPHISMS IN THE HUMAN TUMOR-NECROSIS-FACTOR-ALPHA GENE PROMOTER

We have identified three new human tumor necrosis factor-or (TNF-alpha promoter polymorphisms with single nucleotide (nt) substitutions at - 862, -856, and -574 nt relative to the TNF-alpha transcription start s ite. The -862 and -856 nt TNF-alpha promoter polymorphisms occur with. high frequency in Caucasian and Cambodian individuals and are each no n-randomly associated with three extended HLA haplotypes. This study, in which 61 independent TNF-alpha promoters were analyzed spanning fro m -977 to +93 nt relative to the TNF-alpha mRNA cap site, establishes a new canonical TNF-alpha promoter sequence. Furthermore, we show that none of the three navel polymorphisms at -862, -856 and -574 nt or po lymorphisms previously described at positions -238, -308 and +70 have an effect upon TNF-alpha gene expression in activated lymphocytes. Thu s, these TNF-alpha promoter polymorphisms likely serve as markers for neighboring genes encoding HLA or other undefined molecules in the MHC that may influence disease susceptibility.