Effects of tumor necrosis factor α-857C/T polymorphism on the expression of tumor necrosis factor α.
It was reported that homozygosity for a lymphotoxin α (LTA) 1-1-1-1 haplotype (LTA NcoI-TNFc-aa13L-aa26) may identify subgroups with a poor response to infliximab in Crohn's disease patients. Previously, we found a genetic polymorphism that linked with the LTA 1-1-1-1 haplotype and noted that it was a tumor necrosis factor (TNF) α-857 T allele. To investigate the effects of the -857C/T (rs1799724) polymorphism on the expression of TNFα, we compared levels of transcriptional activity of the gene, mRNA, and protein of the TNFα. The change in transcriptional activity of the -857T allele was higher than that of the -857C allele. Furthermore, the accumulated transcriptional activity of the -857T allele was 1.3-fold higher than that of the -857C allele up to 48 h. The levels of mRNA and protein of the TNFα after stimulation were also shown to be significantly higher in -857C/T as compared to the -857C/C genotype. Our results suggested that TNFα promoter -857T is higher than -857C in the levels of transcriptional activity of the gene, mRNA, and protein of the TNFα. The differences in therapeutic effect of TNF inhibitors among individuals can be explained in part by the induction ability of TNFα via the -857C/T polymorphism.
Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
Koji
K
Kimura
Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
Risa
R
Takayanagi
Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
Haruko
H
Yokoyama
Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
Yasuhiko
Y
Yamada
D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha
Infliximab; enzyme-linked immunosorbent assay; reporter gene assay; reverse transcription-polymerase chain reaction; tumor necrosis factor α