Genetic variability at the human tumor necrosis factor loci.
Variability in the structure of the human tumor necrosis factor (TNF-alpha) or lymphotoxin (TNF-beta) genes may contribute to the functional polymorphism of the HLA gene complex. We have characterized an allelic restriction fragment length polymorphism (RFLP) of the TNF-beta gene by using the restriction endonuclease NcoI. Digestion of genomic DNA with NcoI and Southern blotting by using TNF-alpha gene probes show 5.4-kb and 10.5-kb hybridizing fragments. In Caucasian populations, the 10.5-kb fragment is present in 64 to 72% of haplotypes. The polymorphic NcoI site is located within the first intron of the TNF-beta gene. Additional restriction fragment variability was demonstrated by digestion with AccI; however, this restriction fragment variability was not allelic in nature. Rather, it was a consequence of variable DNA methylation at AccI sites within and upstream of the TNF-beta gene. In peripheral blood leukocytes, methylation of the TNF-beta AccI sites was greatest in neutrophils (TNF-beta nonproducers), and lowest in T lymphocytes (the major producers of TNF-beta). These results suggest strongly that variation in DNA methylation may play an important role in regulation of the expression of the TNF-beta gene.
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110.
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Webb
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Chaplin
D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D002874:Chromosome Mapping; D004247:DNA / Q000378:metabolism; D006801:Humans; D008745:Methylation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D001374:Azacitidine