Blood DNA methylation sites predict death risk in a longitudinal study of 12,300 individuals
Blood DNA methylation sites predict death risk in a longitudinal study of 12,300 individuals
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DOI：
10.18632/aging.103408
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发表时间：
2020-07-31
期刊：
影响因子：
5.2
通讯作者：
Baccarelli, Andrea
中科院分区：
文献类型：
--
作者：
Colicino, Elena;Marioni, Riccardo;Baccarelli, Andrea
DNA甲基化在基因编程和衰老中起着重要作用，可能有助于预测死亡率。然而，没有大规模的研究调查位点特异性DNA甲基化是否预测全因死亡率。我们使用Illumina-HumanMethylation450-BeadChip来鉴定与遗传流行病学心脏与衰老研究（CHARGE）联盟的12个队列中12,300名参与者的全因死亡率相关的血液DNA甲基化位点。在平均10年的随访中，整个队列中有2561人死亡。9个定位于3个基因间区域和6个基因特异性区域的位点与死亡率相关（P < 9.3x10-7），独立于年龄和其他死亡率预测因子。6个位点（cg14866069、cg23666362、cg20045320、cg07839457、cg07677157、cg09615688）分别定位于BMPR1B、MIR1973、IFITM3、NLRC5和2个基因间区，与降低死亡风险相关。其余3个位点（cg17086398、cg12619262、cg18424841）分别定位于SERINC2、CHST12和一个基因间区，与死亡风险增加相关。每个位点的DNA甲基化预测了5%-15%的死亡。我们还通过孟德尔随机化评估了这些位点与年龄相关慢性疾病的因果关系，发现cg18424841和cg09615688与冠心病之间存在弱因果关系。在先前的CHARGE分析中，9个位点中有3个（cg20045320、cg07839457、cg07677157）与较低的心脏病风险发生率相关，2个（cg20045320、cg07839457）与吸烟和炎症相关。cg20045320、cg07839457和cg17086398的甲基化与与免疫应答和心脏代谢疾病相关的附近基因（IFITM3、IRF、NLRC5、MT1、MT2、MARCKSL1）的表达降低相关。这些站点可作为死亡率风险评估和预防性护理的有用临床工具。
DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.