Modulation of human longevity by SIRT3 single nucleotide polymorphisms in the prospective study "Treviso Longeva (TRELONG)"
Modulation of human longevity by SIRT3 single nucleotide polymorphisms in the prospective study "Treviso Longeva (TRELONG)"
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DOI：
10.1007/s11357-013-9559-2
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发表时间：
2014-02-01
期刊：
影响因子：
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通讯作者：
Forloni, Gianluigi
中科院分区：
文献类型：
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作者：
Albani, Diego;Ateri, Eleonora;Forloni, Gianluigi
人类沉默调节蛋白是七种具有脱乙酰酶活性的蛋白质，它们正在成为基本生理功能的关键调节剂。一些证据将 SIRT3 与哺乳动物的长寿联系起来。本研究旨在调查 SIRT3 基因内的变异是否与人类长寿相关。我们分析了前瞻性研究“Treviso Longeva”期间收集的 549 份基因组 DNA，其中包括来自意大利东北部小城市特雷维索市的 70 岁以上老年人。我们通过实时聚合酶链反应等位基因区分测定对 SIRT3 rs3825075、rs4980329 和 rs11555236 单核苷酸多态性 (SNP) 进行基因分型。通过比较 85 岁以上和 85 岁以下人群进行的横断面分析并未证明 SIRT3 SNP 与长寿之间存在关联。然而，当我们将死亡率作为因变量进行纵向分析时，我们观察到 SIRT3 rs11555236 和 rs4980329 与整个人群的寿命之间存在关联（针对潜在混杂因素进行校正的 p 值分别为 0.04 和 0.03）。根据性别分层后，相同的 SNP 仅与女性寿命相关（潜在混杂因素校正后的 p 值分别 = 0.03 和 0.02）。最后，由于据报道 rs11555236 与 SIRT3 基因内推定的功能增强子连锁不平衡，我们评估了 rs11555236 基因型是否与外周血单核细胞中不同水平的 SIRT3 蛋白相关。我们发现 (T) 等位基因纯合受试者的 SIRT3 水平升高。我们认为 SIRT3 遗传变异可能与意大利人群寿命的调节有关。
Human sirtuins are seven proteins with deacetylase activity that are emerging as key modulators of basic physiological functions. Some evidence links SIRT3 to longevity in mammals. This study aimed to investigate whether variants within SIRT3 gene were associated to human longevity. We analyzed 549 genomic DNA collected during the prospective study "Treviso Longeva," including elderly over 70 years of age from the municipality of Treviso, a small city in the northeast of Italy. We genotyped SIRT3 rs3825075, rs4980329, and rs11555236 single nucleotide polymorphisms (SNPs) by real-time polymerase chain reaction allelic discrimination assay. A cross-sectional analysis performed by comparing people over and under 85 years of age did not evidence association among the SIRT3 SNPs and longevity. However, when we performed a longitudinal analysis considering mortality as a dependent variable, we observed an association of SIRT3 rs11555236 and rs4980329 with longevity in the whole population (p values corrected for potential confounders = 0.04 and 0.03, respectively). After stratification according to gender, the same SNPs were associated to female longevity only (p values corrected for potential confounders = 0.03 and 0.02, respectively). Finally, as rs11555236 was reported to be in linkage disequilibrium with a putative functional enhancer within the SIRT3 gene, we assessed whether rs11555236 genotypes correlated with a different level of SIRT3 protein in peripheral blood mononuclear cells. We found an increased level of SIRT3 in subjects homozygous for the (T) allele. We suggest that SIRT3 genetic variability might be relevant for the modulation of human longevity in the Italian population.