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

Narcolepsy is a sleep disorder in which multiple factors, including environ mental and genetic factors, are involved. a genetic factor strongly associa ted with the disorder has been found in the human leukocyte antigen (HLA) c lass II region: the haplotype, DRB1*150I-DQB1*0602, predisposes to narcolep sy. 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 narc olepsy,in which we examined the known single-nucleotide polymorphisms (SNPs ) in the promoter region in 49 narcoleptic patients, who were all positive for DRB1*1501, and 111 healthy control individuals. The re suits indicated that the frequency of the genotype at position -857 (-857SNP) was significa ntly different between the patients and controls, and the allele frequencie s of -857SNP revealed that the frequency of -857T was significantly increas ed in the patients as compared with that in the controls (P=0.0068). In add ition, haplotypes presumed from HLA-DRB1, -857SNP and HLA-B loci suggested that -857 T was mainly associated with DRB1 alleles other than DRB1*1501:th e significant increase in frequently of -857T in the patients was not cause d by allelic association with DRB1*1501. Therefore, it is conceivable that the TNF-alpha with -857T was associated with narcolepsy independently of th e strong association of DRB1*1501 with the disorder. Altogether, the data p resented here lead us to propose that TNF-alpha could be a new susceptibili ty gene in human narcolepsy.