Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor‐α gene promoter

Abstract

We have identified three new human tumor necrosis factor-alpha (TNF-alpha) promoter polymorphisms with single nucleotide (nt) substitutions at -862, -856, and -574 nt relative to the TNF-alpha transcription start site. The -862 and -856 nt TNF-alpha promoter polymorphisms occur with high frequency in Caucasian and Cambodian individuals and are each non-randomly associated with three extended HLA haplotypes. This study, in which 61 independent TNF-alpha promoters were analyzed spanning from -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 novel polymorphisms at -862, -856 and -574 nt or polymorphisms previously described at positions -238, -308 and +70 have an effect upon TNF-alpha gene expression in activated lymphocytes. Thus, 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.

An analysis of tumor necrosis factor α gene polymorphisms and haplotypes with natural clearance of hepatitis C virus infection

“…Comparison of the À863A allele to the À863C has linked À863A to a spectrum of effects including reduced circulating levels of TNF-a, 24 increased TNF-a production by stimulated PBMCs, 25 and no effect on TNF-a gene expression. 26 These disparate results suggest that the net effect of variants in the promoter region varies according to which of the multiple transcription factors binds to it. The ubiquitous transcription factor OCT-1 has increased binding to the TNF promoter in the presence of the À863A allele.…”

“…Studies using gene reporter assays have also shown effects ranging from increased 33 to no change 26,34 in gene transcription. Since these studies use different approaches, it is difficult to compare them to determine the effect of À308A on TNF-a production.…”

Is there a future for TNF promoter polymorphisms?

“…Therefore, attention has focused on the TNF promoter, encouraged by the identification of a number of singlenucleotide polymorphisms (SNPs). Eight DNA variants or 'SNPs' have been described within the TNF promoter, at positions À1031T/C, À863C/A, À857C/T, À575G/A, À376G/A, À308G/A, À244G/A, and À238G/A [10][11][12][13][14][15][16] relative to the transcription start site (Figure 1). The interest in these genetic variants derives from the possibility that the genetic changes they introduce, in comparison to the common form, could affect the binding of transcription factors, controlling the activity of the promoter and resulting mRNA and protein levels.…”

Association of tumor necrosis factor α polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort

“…However, other investigators have not found any functional significance of the -308 G-to-A substitution (36)(37)(38). The conflicting results may be due to differences in the cell lines assessed and the physiologic stimulators used to induce differential transcriptional activity (34).…”