Significant association of a single nucleotide polymorphism in the tumor necrosis factor-alpha (TNF-α) gene promoter with human narcolepsy

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.