血液表观遗传衰老速度的全基因组关联研究揭示了 TERT 的关键作用。
GWAS of epigenetic aging rates in blood reveals a critical role for TERT.
机构信息
Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
出版信息
Nat Commun. 2018 Jan 26;9(1):387. doi: 10.1038/s41467-017-02697-5.
DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.
DNA 甲基化年龄是一个准确的生物学年龄标志物，可以预测寿命，但它的潜在分子机制尚不清楚。在这项对 9907 个人的全基因组关联研究中，我们发现了五个与内在表观遗传年龄加速（IEAA）相关的基因变异，以及三个与外在表观遗传年龄加速（EEAA）相关的基因变异。孟德尔随机化分析表明，月经初潮和绝经期对 IEAA 的影响，以及脂蛋白对 IEAA 和 EEAA 的影响具有因果关系。在端粒酶逆转录酶基因（TERT）中与白细胞端粒长度（LTL）延长相关的变异体反而导致更高的 IEAA（P < 2.7 × 10）。因果建模表明，TERT 对 LTL 和 IEAA 有特定和独立的影响。在原代人成纤维细胞中的 hTERT 表达实验导致 DNA 甲基化年龄随细胞群体倍增数呈线性增加。这些发现表明，hTERT 在调节表观遗传钟方面具有重要作用，除了其补偿细胞复制相关的端粒缩短的既定作用。
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