长寿老人SIRT6基因的罕见及常见变异研究

目的 SIRT6基因属于Sirtuin家族的一员,是长寿候选基因.本文旨在长寿老人中探索SIRT6基因的罕见及常见变异分布情况.方法 从如皋长寿及衰老队列的长寿组中随机抽取102例长寿老人(≥95岁),对SIRT6基因的启动子及外显子区域进行PCR扩增和直接测序,识别罕见及常见变异,并与千人基因组中汉族人群数据进行频率比对.结果 总共完成约10 kb的测序,覆盖了SIRT6基因的8个外显子和1.5kb的启动子区域.在发现的20个已报道变异位点中,6个分布在启动子区,1个分布在外显子上,2个分布在3'UTR区域,11个分布在内含子区.共有12个已报道变异位点的最小等位基因频率(minor allele frequencies,MAFs)超过0.05;其中,rs352493(MAF=0.245)为非同义突变.在剩下8个MAF低于0.05的已报道位点中,rs117541451 (MAF=0.010)和rs146420357(MAF=0.029)与千人基因组中汉族人相应频率差异具有统计学意义(P=0.021).观察到5个新发位点,其MAF均为0.005.这5个位点中,有1个分布在外显子上,1个分布在启动子区,1个分布在3'UTR区域,2个则分布在内含子区.结论 在如皋长寿人群SIRT6基因上首次观察到20个已报道变异位点(12个为常见位点)及5个新发位点(均为罕见位点).这为长寿的遗传学探索及功能研究提供了新的重要候选位点,进一步强调了罕见变异在长寿中的重要作用.

Identification of rare and common variants of SIRT6 gene in long-lived individuals

Objective SIRT6,a member of sirtuin family,is a candidate gene of longevity.This study aimed to investigate rare and common variants of the SIRT6 gene in long-lived individuals.Methods Overall 102 long-lived individuals aged 95 years and older were randomly sampled from the longevity group of the Rugao Longevity and Aging Study (RuLAS).The promoter and exon regions of the SIRT6 gene were amplified and sequenced to identify rare and common variants.The allele frequencies of variants in study subjects were compared with those in Han Chinese population in the 1000 Genome Project.Results Approximately 10 kb of the SIRT6 gene regions were sequenced,which covered all the 8 exons and 1.5 kb promoter.Twenty reported variants were identified in the study participants,including six variants in promoter,one variant in exons,two variants in 3'UTR,and eleven variants in introns.There were twelve reported variants with minor allele frequencies (MAFs) over 0.05,with rs352493 (MAF =0.245) being the a nonsynonymous variant.Within the 8 variants with MAF ＜ 0.05,we observed significant differences in allele frequencies of rs 117541451 (MAF =0.010) and rs 146420357 (MAF =0.029) in the study participants,compared to the Han Chinese population in the 1000 Genome Project (P =0.021).Five novel and rare variants (MAF =0.005) were identified in this study,including one variant in exons,one in promoter,one in 3'UTR,and two in introns.Conclusion Overall,we observed twenty reported (twelve common) and five novel (rare) variants in long-lived individuals in Rugao.Our results provide critical candidate variants for further genetic and functional research in longevity,and underscore the importance of rare variants promoting longevity.