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障碍。在这项研究中，我们将发作性睡病作为一种睡眠障碍，将睡眠相延迟综合征(DSPS)和非24小时睡眠觉醒综合征(Non-24)作为昼夜节律障碍，并试图找到这些疾病的遗传因素(基因)。基因关联研究以易患疾病的候选基因的核苷酸变异为标记。简单地说，为了寻找这些候选基因的核苷酸变化，我们利用PCR-SSCP和PCR-直接测序的方法进行了变异筛选，并将所产生的核苷酸变化作为标记用于病例和对照的基因分型。使用分型数据，我们检查了疾病与所调查的候选基因之间是否存在任何关联。这项研究的结果表明，人类发作性睡病与…提示肿瘤坏死因子-α-α受体2信号转导通路可能参与了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肿瘤坏死因子-α基因启动子上的功能性单核苷酸多态(Q3NP)结合。这提示OCT-1与这些功能α位点的等位基因特异性结合所调节的肿瘤坏死因子-SNP表达水平可能影响人类发作性睡病的易感性。在这项研究中需要注意的另一个发现是，携带DRB1^*1502-DQB1^*0601的人类白细胞抗原(HLA)单倍型与人类发作性睡病呈负相关。到目前为止，我们研究了c-Fos和N-乙酰转移酶(NAT2)基因，但没有发现与这种疾病相关的基因。还需要进一步的研究。较少

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