2001 Fiscal Year Final Research Report Summary
Search for genetic factors associated with sleep and circadian rhythm disorders
| Project/Area Number |
12672198
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human genetics
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| Research Institution | The University of Tokyo |
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Principal Investigator |
HOHJOH Hirohiko The University of Tokyo, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 助手 (60238722)
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| Co-Investigator(Kenkyū-buntansha) |
TOKUNAGA Katsushi The University of Tokyo, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (40163977)
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| Project Period (FY) |
2000 – 2001
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| Keywords | sleep and circadian rhythm disorders / Narcolepsy / Geve association study / TNF-α / TNFR1 / TNFR2 |
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| Research Abstract |
Sleep and circadian rhythm disorders are thought to be multifactorial disordes involving various genetic and environmental factors. In this study, we investigated narcolepsy as a sleep disorder and delayed sleep phase syndrome (DSPS) and non-24-hour sleep wake syndrome (Non-24) as circadian rhythm disorders, and attempted to find genetic factors (genes) predisposing to these disorders. Gene association study was carried out using nucleotide variations in candidate genes for predisposing to the disorders as markers. Briefly, to search for nucleotide changes in such candidate genes, variation screening was carried out by means of PCR-SSCP and PCR-direct sequencing, and resultant nucleotide changes were used as markers in genotyping of the cases and controls. Using the typing data, we examined if there were any associations between the disorders and candidate genes investigated. The results in this study indicate that there is a significant association between human narcolepsy and either
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tumor necrosis factor-alpha (TNF-α) or TNF-α receptor 2 (TNFR2) gene, suggesting that the TNF-α-TNFR2 signal-transduction pathway could participate in the pathogenesis and pathophysiology of human narcolepsy. We further demonstrated that the ubiquitous transcription factor OCT-1 could bind to the functional single nucleotide polymorphism Q3NP) sites in the TNF-α gene promoter in an allele-specific manner. This suggest the possibility that the TNF-αexpression level modulated by the allelespecific binding of OCT-1 to such functional SNP sites could influence the predisposition to human narcolepsy. Another finding to note in this study is that the human leukocyte antigen (HLA) haplotype carrying DRB1^*1502-DQB1^*0601 has a negative association with human narcolepsy. This leads to the hypothesis that the haplotype could confer protection against narcolepsy.
As for the genetic factors predisposing to DSPS and Non-24, we have so far investigated c-Fos and N-acetyltransferase (NAT2) genes without association with the disorder. Further studies are required. Less
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