Szekely2017PLoS_LongevityDatabase.sav

Longevity is in part (25%) inherited, and genetic studies aim to uncover allelic variants that play an important role in prolonging life span. Results to date confirm only a few gene variants associated with longevity, while others show inconsistent results. However, GWAS studies concentrate on single nucleotide polymorphisms, and there are only a handful of studies investigating variable number of tandem repeat variations related to longevity. Recently, Grady and colleagues (2013) reported a remarkable (66%) accumulation of those carrying the 7 repeat allele of the dopamine D4 receptor gene in a large population of 90-109 years old Californian centenarians, as compared to an ancestry-matched young population. In the present study we demonstrate the same association using continuous age groups in an 18-97 years old Caucasian sample (N=1801, p=0.007). We found a continuous pattern of increase from 18-75, however frequency of allele 7 carriers decreased in our oldest age groups. Possible role of gene-environment interaction effects driven by historical events are discussed. In accordance with previous findings, we observed association preferentially in females (p=0.003). Our results underlie the importance of investigating non-disease related genetic variants as inherited components of longevity, and confirm, that the 7-repeat allele of the dopamine D4 receptor gene is a longevity enabling genetic factor, accumulating in the elderly female population.

长寿在一定程度上（25%）具有遗传性，遗传研究旨在揭示在延长寿命过程中发挥重要作用的等位基因变异体。迄今为止的研究结果仅证实了少数与长寿相关的基因变异，其余相关研究结论则存在不一致性。不过，全基因组关联研究（Genome-Wide Association Study, GWAS）主要聚焦于单核苷酸多态性，目前仅有少量研究探讨与长寿相关的可变数目串联重复序列变异。近期，Grady及其团队（2013年）在一项针对加州90至109岁百岁老人的大样本研究中发现，与祖先匹配的年轻人群相比，携带多巴胺D4受体基因7次重复等位基因的个体占比显著提升（达66%）。本研究针对18至97岁的高加索人群样本（N=1801，p=0.007）采用连续年龄分组的方式，验证了这一关联关系。研究团队观察到，从18岁至75岁，7次重复等位基因携带者的频率呈持续上升趋势，但在最年长的年龄组中该频率出现下降。本研究还探讨了由历史事件驱动的基因-环境交互作用可能发挥的作用。与既往研究结果一致，本研究观察到该关联在女性群体中更为显著（p=0.003）。本研究结果凸显了将非疾病相关遗传变异作为长寿遗传组分进行研究的重要性，并证实多巴胺D4受体基因7次重复等位基因是一种可促进长寿的遗传因子，在老年女性群体中呈现富集现象。