认知相关遗传变异及其与环境的交互作用对长寿人群认知功能的影响

Cognition may decline or even impair with advancing age. Environmental coupled with genetic factors are believed to determine the process of cognition decline. However, data in this field are mainly based on population with cognitive impairment, little is available from successful aging cohorts. Famous for its longevity, Guangxi Bama has been established as an important research base for human aging. Our previous NNSF project results showed that Bama long-lived individuals exhibited excellent cognition and activities of daily life (ADL), with lower prevalence of cognition disturbance and lower frequency of cognitive detrimental genetic variants. However, current data can not fully interpret the cognitive advantage for Bama long-lived population. Herein, we seek to carry out a longitudinal study for this cohort in order to further understand their dynamic change of cognition and relevant external environments. We also perform a large scale of cognitive-associated variant screen for them according to the most recent published data from genome-wide association study (GWAS) and exome-wide association discovery study. Basing on these information and bioinformatics, we hope to further unravel the potential protective factors which may contribute to the better cognition and the successful aging in Bama oldest olds through comprehensive analyses of gene-gene and gene-environment interaction. The research results may be promising in further understanding the etiology and pathogenesis of aging and maybe significant in the attenuation and protection of age-associated disorders such as cognitive impairment.

衰老过程常伴有认知水平下降甚至出现认知障碍性疾病，环境和遗传因素可能共同影响认知障碍进程，但此方面的资料多基于认知障碍疾病的群体模型，鲜见健康长寿群体的报道。广西巴马因长寿而闻名，是研究认知衰老的重要基地。我们的前期研究显示巴马长寿老人的认知及日常生活能力良好，认知障碍发生率低，个别认知障碍相关变异的频率较低，但现有数据仍无法完全诠释其认知优势。本项目拟对该群体进行纵向研究，对长寿群体的认知水平、日常生活活动及环境因素进行多维度随访追踪调查并综合分析，同时根据GWAS及外显子组学最新报道选定候选基因，大规模检测认知相关基因的多态性，并采用生物信息学方法，分析基因-基因及基因-环境因素的交互作用对长寿群体认知的影响，进一步揭示健康长寿人群中认知功能潜在的保护性因素。研究的结果可望有助了解认知衰老的原因及机制，对减缓或防治认知减退等衰老性疾病有潜在的意义。

认知功能减退是机体衰老进程中的重要表现之一，故亦称认知衰老。不同个体之间的认知衰老过程和程度差别较大，其中，很多健康长寿的个体不仅有正常的日常活动能力，还保持着较高的认知水平，推测可能有潜在的遗传学优势及良好的生活方式。在长寿群体中探讨认知衰老的机制，更有望了解维持正常认知的保护因素或触发认知障碍的易感因素，延缓认知衰老进程，提高老年人的生活质量。本项目应用TaqMan和iMLDR技术对广西巴马县及其周围县份长寿人群的认知衰老相关单核苷酸多态(SNPs)进行分型，然后使用GMDR等统计遗传学软件分析这些SNPs之间以及SNPs与血压、BMI、血糖、血脂等认知损害危险因素之间的交互作用对认知衰老的影响。目前取得的主要结果如下：（1）多数长寿老人的认知水平及日常生活活动能力良好，认知障碍的发生率较低。（2）长寿老人及其子女的血压、血糖、TC、TG、LDL-C、Apo B等认知障碍危险因素的水平显著低于普通老年人。（3）长寿人群及其子女中携带rs1439568 TT基因型的个体与认知障碍有关。（4）GMDR分析显示，rs2313148、rs3851179、rs5882、rs6265、rs670139之间，以及rs12621515、rs2313148、rs3027247、rs3851179、rs5882、rs6265、rs670139、SBP、LDL-C之间存在基因-基因和基因-环境间的交互作用，其中rs2313148和rs3027247之间以及rs3851179和LDL-C之间分别存在最强的基因-基因、基因-环境协同作用。携带rs2313148 CC、rs3027247 CC/CA基因型和携带rs2313148 CT/TT、rs3027247 AA基因型可能会降低长寿老人的认知功能。以上结果提示，某些基因之间，或这些基因与血压、血脂等环境因素之间的交互作用，共同影响认知衰老的进程。