Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer's disease and longevity in an Italian population

Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant "zeitgeber" able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.人体诸多生理过程均受昼夜节律钟系统调控，呈现以24小时为周期的昼夜节律（circadian rhythm）。视网膜感知的光线是最主要的授时因子（zeitgeber），可将昼夜节律同步至光暗循环。昼夜节律紊乱与睡眠障碍已被证实与衰老及多种神经退行性疾病相关，包括轻度认知障碍（MCI）与阿尔茨海默病（AD）。本研究旨在探究意大利籍阿尔茨海默病患者与健康对照者之间节律基因的遗传变异特征。此外，本研究还纳入了一组意大利百岁老人作为超级对照（super-controls）——因其具备成功衰老的极端表型，在关联研究中常被用作优质对照。我们对84个与昼夜节律相关的基因的外显子序列进行了测序分析，在首轮发现阶段鉴定出的具有统计学显著性的变异位点，进一步通过基质辅助激光解吸电离飞行时间质谱技术，在更大规模的独立阿尔茨海默病患者队列中完成了验证。研究结果显示，PER1昼夜节律基因中的rs3027178多态性与阿尔茨海默病存在显著关联，其中G等位基因对阿尔茨海默病具有保护作用。值得注意的是，rs3027178在阿尔茨海默病患者与百岁老人群体中展现出相似的基因型频率。本研究结果共同证实了昼夜节律功能异常在阿尔茨海默病易感性中的重要意义，并为探讨年龄相关疾病遗传学与长寿遗传学之间的关联提供了新的研究视角。