Escola de Artes, Ciências e Humanidades, Universidade de São Paulo, São Paulo, SP Brazil.
Genet Mol Biol. 2010 Oct;33(4):627-32. doi: 10.1590/S1415-47572010005000092. Epub 2010 Dec 1.
Several studies have shown that mutations and polymorphisms in clock genes are associated with abnormal circadian parameters in humans and also with more subtle non-pathological phenotypes like chronotypes. However, there have been conflicting results, and none of these studies analyzed the combined effects of more than one clock gene. Up to date, association studies in humans have focused on the analysis of only one clock gene per study. Since these genes encode proteins that physically interact with each other, combinations of polymorphisms in different clock genes could have a synergistic or an inhibitory effect upon circadian phenotypes. In the present study, we analyzed the combined effects of four polymorphisms in four clock genes (Per2, Per3, Clock and Bmal1) in people with extreme diurnal preferences (morning or evening). We found that a specific combination of polymorphisms in these genes is more frequent in people who have a morning preference for activity and there is a different combination in individuals with an evening preference for activity. Taken together, these results show that it is possible to detect clock gene interactions associated with human circadian phenotypes and bring an innovative idea of building a clock gene variation map that may be applied to human circadian biology.
几项研究表明，时钟基因的突变和多态性与人类昼夜节律参数异常有关，也与更微妙的非病理表型（如昼夜类型）有关。然而，这些研究的结果存在冲突，而且没有一项研究分析了一个以上时钟基因的综合效应。迄今为止，人类的关联研究仅集中于对每个研究中的一个时钟基因进行分析。由于这些基因编码的蛋白质相互物理作用，不同时钟基因中的多态性组合可能对昼夜节律表型具有协同或抑制作用。在本研究中，我们分析了四个时钟基因（Per2、Per3、Clock 和 Bmal1）中的四个多态性在昼夜节律偏好极端的人群（早晨或晚上）中的综合效应。我们发现，具有活动晨型偏好的人群中这些基因的特定多态性组合更为常见，而具有活动晚型偏好的个体则存在不同的组合。总之，这些结果表明，有可能检测到与人类昼夜节律表型相关的时钟基因相互作用，并提出了构建时钟基因变异图谱的创新思路，该图谱可能应用于人类昼夜节律生物学。
