The rs2802292, rs2764264 and rs13217795 variants of FOXO3 have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing of the FOXO3 gene. We performed a comprehensive assessment of FOXO3 isoform usage across a wide variety of human tissues and carried out a bioinformatic analysis of the potential for longevity-associated variants to disrupt regulatory regions involved in isoform choice. We then related the expression of full length and 5′ truncated FOXO3 isoforms to rs13217795 genotype in peripheral blood and skeletal muscle from individuals of different rs13217795 genotypes. FOXO3 isoforms displayed considerable tissue specificity. We determined that rs13231195 and its tightly aligned proxy variant rs9400239 may lie in regulatory regions involved in isoform choice. The longevity allele at rs13217795 was associated with increased levels of full length FOXO3 isoforms in peripheral blood and a decrease in truncated FOXO3 isoforms in skeletal muscle RNA. We suggest that the longevity effect of FOXO3 SNPs may in part derive from a shift in isoform usage in skeletal muscle away from the production of 5′ truncated FOXO3 isoforms lacking a complete forkhead DNA binding domain, which may have compromised functionality.

FOXO3 的 rs2802292、rs2764264 和 rs13217795 变体与多个人群的极端长寿有关，但其背后的机制仍不清楚。我们旨在描述长寿相关变异对FOXO3基因表达和 mRNA 加工的潜在影响。我们对多种人体组织中FOXO3异构体的使用进行了全面评估，并对长寿相关变体破坏参与异构体选择的调节区域的潜力进行了生物信息学分析。然后我们将全长和 5' 截断FOXO3的表达联系起来来自不同 rs13217795 基因型个体的外周血和骨骼肌中 rs13217795 基因型的亚型。FOXO3亚型显示出相当大的组织特异性。我们确定 rs13231195 及其紧密对齐的代理变体 rs9400239 可能位于参与异构体选择的调节区域。rs13217795 的长寿等位基因与外周血中全长FOXO3同种型水平的增加和骨骼肌 RNA中截短的FOXO3同种型的减少有关。我们认为FOXO3 SNP 的长寿效应可能部分源于骨骼肌中亚型使用的转变，远离 5' 截短FOXO3的产生亚型缺乏完整的叉头 DNA 结合域，这可能会损害功能。