title: Significant association of a single nucleotide polymorphism in the tumor necrosis factor-alpha (TNF-alpha) gene promoter with human narcolepsy.
abstract: Narcolepsy is a sleep disorder in which multiple factors, including environmental and genetic factors, are involved. A genetic factor strongly associated with the disorder has been found in the human leukocyte antigen (HLA) class II region: the haplotype, DRB1*1501-DQB1*0602, predisposes to narcolepsy. No susceptibility genes other than the HLA-haplotype have been found. In this paper, we performed an association study of the tumor necrosis factor-alpha (TNF-alpha) gene located in the HLA class III region with human narcolepsy, in which we examined the known single-nucleotide polymorphisms (SNPs) in the promoter region in 49 narcoleptic patients, who were all positive for DRBI*1501, and 111 healthy control individuals. The results indicated that the frequency of the genotype at position -857 (-857SNP) was significantly different between the patients and controls, and the allele frequencies of 857SNP revealed that the frequency of -857T was significantly increased in the patients as compared with that in the controls (P=0.0068). In addition, haplotypes presumed from HLA-DRB1, -857SNP and HLA-B loci suggested that -857T was mainly associated with DRB1 alleles other than DRB1*1501: the significant increase in frequency of -857T in the patients was not caused by allelic association with DRB1*1501. Therefore, it is conceivable that the TNF-alpha with 857T was associated with narcolepsy independently of the strong association of DRB1*1501 with the disorder. Altogether, the data presented here lead us to propose that TNF-alpha could be a new susceptibility gene in human narcolepsy.
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Japan. hohjohh@m.tokyo.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Hohjoh
authors.forename: T
authors.initials: T
authors.lastname: Nakayama
authors.forename: J
authors.initials: J
authors.lastname: Ohashi
authors.forename: T
authors.initials: T
authors.lastname: Miyagawa
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Akaza
authors.forename: Y
authors.initials: Y
authors.lastname: Honda
authors.forename: T
authors.initials: T
authors.lastname: Juji
authors.forename: K
authors.initials: K
authors.lastname: Tokunaga
mesh_terms: D000483:Alleles; D005260:Female; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D009290:Narcolepsy / Q000235:genetics*; D009711:Nucleotides / Q000235:genetics* / Q000302:isolation & purification; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D009711:Nucleotides; D014409:Tumor Necrosis Factor-alpha