Search for genetic factors associated with sleep and circadian rhythm disorders

睡眠和昼夜节律紊乱被认为是涉及各种遗传和环境因素的多因素紊乱。在这项研究中，我们调查了作为睡眠障碍的发作性睡病和作为昼夜节律障碍的睡眠时相延迟综合征（DSPS）和非24小时睡眠觉醒综合征（Non-24），并试图找到这些疾病的遗传因素（基因）。基因关联研究是利用易感基因中的核苷酸变异作为标记进行的。简言之，为了寻找这些候选基因中的核苷酸变化，通过PCR-SSCP和PCR直接测序进行变异筛选，并将所得核苷酸变化用作病例和对照的基因分型的标记。使用分型数据，我们检查了疾病和候选基因之间是否存在任何关联。这项研究的结果表明，人类嗜睡症与以下两者之间存在显著关联： 关于我们 肿瘤坏死因子-α（TNF-α）或肿瘤坏死因子-α受体2（TNFR 2）基因，提示TNF-α-TNFR 2信号转导通路可能参与了人类发作性睡病的发病机制和病理生理过程。我们进一步证明了普遍存在的转录因子OCT-1可以以等位基因特异性的方式与TNF-α基因启动子中的功能性单核苷酸多态性位点（Q3 NP）结合。这表明OCT-1与这些功能性SNP位点的等位基因特异性结合调节的TNF-α表达水平可能影响人类嗜睡症的易感性。本研究中另一个值得注意的发现是，携带DRB 1 ^*1502-DQB 1 ^*0601的人类白细胞抗原（HLA）单倍型与人类嗜睡症呈负相关。至于易感DSPS和Non-24的遗传因素，迄今为止，我们已经研究了c-Fos和N-乙酰转移酶（NAT 2）基因，但与疾病无关。需要进一步研究。少

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 … More 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