Polymorphisms in the tumor necrosis factor (TNF) genes are associated with susceptibility to effects of ultraviolet-B radiation on induction of contact hypersensitivity.
We investigated the allelic distributions of single nucleotide polymorphisms (SNPs) of the TNFA, TNFB and IKBL genes, 3 microsatellites within the tumor necrosis factor (TNF) region of HLA locus, and the HLA phenotypes as well as the TLR4 gene in Chromosome 9 in 26 healthy Caucasian volunteers. These individuals were also assessed as ultraviolet B (UVB)-susceptible (S) or UVB-resistant (R). Our results identified 12 UVB-S and 14 UVB-R individuals. Attempts to correlate particular HLA-A, -B, -C, and -DR antigens with the UVB phenotypes failed. Similarly, attempts to correlate SNP at the NcoI-RFLP within intron 1 of the TNFB, IKBL and TLR4 gene with UVB phenotypes also failed. However, microsatellite analyses of TNFa, TNFc, and TNFd markers revealed a significant increase in the frequencies of TNFa2 in UVB-S individuals (P=0.00032) and of TNFd3 in UVB-R individuals (P=0.012). Moreover, DNA sequencing analyses of 5 SNPs of the TNFA promoter region revealed a significant increase in the frequency of the allele B of the TNFA gene (TNFApB) representing the nucleotide A at position -863 and C at position -1031 (P=0.015). Since it is known that TNFa2 and TNFApB is a high TNF-alpha responder, whereas TNFd3 is a TNF-alpha low responder, we propose that the TNF region of HLA contains polymorphic genes that confer susceptibility and resistance to the deleterious effects of UVB radiation on the induction of contact hypersensitivity. This proposal is consistent with previous reports that a unique microsatellite region of the Tnfa gene in mice contains alleles that dictate the UVB-dependent phenotypes in mice, and implicate TNF-alpha as the primary mediator of the immune-damaging effects of UVB radiation.
Niizeki
H
H
Department of Dermatology, Clinical Research Institute, National Tokyo Medical Center, 2-5-1 Higeshi-ga-oka, Meguro, Tokyo 152-8902, Japan. hniizeki@ntmc.hosp.go.jp
Naruse
T
T
Hecker
K H
KH
Taylor
J R
JR
Kurimoto
I
I
Shimizu
T
T
Yamasaki
Y
Y
Inoko
H
H
Streilein
J W
JW
D048868:Adaptor Proteins, Signal Transducing; D003877:Dermatitis, Contact / Q000235:genetics* / Q000276:immunology*; D029721:Drosophila Proteins; D005787:Gene Frequency; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006650:Histocompatibility Testing; D006801:Humans; D007107:Immune System / Q000528:radiation effects; D008562:Membrane Glycoproteins / Q000235:genetics; D018895:Microsatellite Repeats; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014466:Ultraviolet Rays
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; C120111:NFKBIL1 protein, human; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha