Effect of longevity genetic variants on the molecular aging rate
Effect of longevity genetic variants on the molecular aging rate
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DOI：
10.1007/s11357-021-00376-4
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发表时间：
2021-05-04
期刊：
影响因子：
5.6
通讯作者：
Sebastiani, Paola
中科院分区：
文献类型：
--
作者：
Gurinovich, Anastasia;Song, Zeyuan;Sebastiani, Paola
我们对来自新英格兰百岁老人研究的1320名百岁老人（中位年龄= 104岁）和2899名无关对照进行了全基因组关联研究，使用>9 M的遗传变异估算到HRC面板上，类似于65，000个单倍型。具有最显著关联的遗传变异与4131种蛋白质相关，这些蛋白质使用SOMAscan阵列在224名研究参与者的血清中进行了分析。在对480名百岁老人和800名德系犹太人后裔进行的全基因组关联研究中，复制了遗传关联。蛋白质组学关联在来自第三队列的大约1000名德系犹太人参与者的蛋白质组学扫描中被复制。该分析复制了与APOE基因型相关的蛋白质特征，并证实了BIRC 2的强过表达（p < 5E-16）和APOE 2等位基因携带者中APOB的低表达（p < 0.05）。该分析还发现并复制了长寿变异与衰老蛋白质生物标志物变化较慢之间的关联，包括一种新的蛋白质特征rs 2184061（9号染色体上的CDKN 2A/CDKN 2B），表明GDF 15的遗传调控。分析表明，长寿变异与蛋白质组特征相关，可以操纵这些特征来发现健康衰老的目标。
We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of similar to 65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and similar to 800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets.