College of Public Health and Human Sciences, Oregon State University, Corvallis.
Bioinformatics Program, Boston University, Massachusetts.
J Gerontol A Biol Sci Med Sci. 2018 Oct 8;73(11):1439-1447. doi: 10.1093/gerona/glx124.
Previous studies note specific FOXO3 single-nucleotide polymorphisms (SNPs) associated with human longevity. However, it is not clear if these SNPs influence mortality risk beyond the oldest 1 percentile of survival. Using data from four longevity studies (total n = 8,266, age range 96-119 years for cases), we tested gene-wide association between 107 SNPs and survival to at least the oldest 1 percentile of survival for the 1900 birth cohort (≥96, white males; ≥100 white females). This analysis replicated 17 previously published variants, several of which are significant expression quantitative trait loci of FOXO3; rs6911407 and rs2253310 have the most significant effect on FOXO3 expressions in brain tissue. We then performed a survival analysis to determine if any of these 107 SNPs impact upon mortality risk beyond the oldest 1 percentile. While none of the 17 published variants was significantly associated with mortality risk beyond this extreme age, an uncommon homozygote genotype of rs9384680 exhibited the strongest association with mortality risk (p = 2.68E-04) in only 11 females, a heretofore unreported association. These analyses replicate the previous association of common variants of FOXO3 with older age but these common variants do not modify risk for mortality at ages beyond the oldest 1 percentile age of survival.
先前的研究指出了特定的 FOXO3 单核苷酸多态性（SNPs）与人类长寿有关。然而，目前尚不清楚这些 SNPs 是否会影响到最长存活期的 1%以后的死亡率。我们使用来自四项长寿研究的数据（总人数为 8266 人，病例年龄范围为 96-119 岁），对 107 个 SNP 与至少最长存活期的 1%的存活相关进行了基因全关联分析。这项分析复制了 17 个先前发表的变体，其中几个是 FOXO3 的显著表达数量性状基因座；rs6911407 和 rs2253310 对脑组织中 FOXO3 的表达影响最大。然后，我们进行了生存分析，以确定这 107 个 SNP 是否会影响最长存活期 1%以后的死亡率。虽然没有一个已发表的 17 个变体与这个极端年龄以后的死亡率有显著相关性，但 rs9384680 的罕见纯合基因型与 11 名女性的死亡率风险之间表现出最强的相关性（p=2.68E-04），这是以前没有报道过的相关性。这些分析复制了之前关于 FOXO3 常见变体与年龄较大的关联，但这些常见变体不会改变最长存活期 1%以后的死亡率风险。
