Age-related clonal hematopoiesis associated with adverse outcomes.
Age-related clonal hematopoiesis associated with adverse outcomes.
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DOI：
10.1056/nejmoa1408617
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发表时间：
2014-12-25
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影响因子：
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通讯作者：
Ebert BL
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作者：
Jaiswal S;Fontanillas P;Flannick J;Manning A;Grauman PV;Mar BG;Lindsley RC;Mermel CH;Burtt N;Chavez A;Higgins JM;Moltchanov V;Kuo FC;Kluk MJ;Henderson B;Kinnunen L;Koistinen HA;Ladenvall C;Getz G;Correa A;Banahan BF;Gabriel S;Kathiresan S;Stringham HM;McCarthy MI;Boehnke M;Tuomilehto J;Haiman C;Groop L;Atzmon G;Wilson JG;Neuberg D;Altshuler D;Ebert BL
血液病的发病率随着年龄的增长而增加。这些癌症与特定基因的复发性体细胞突变有关。我们假设这样的突变可以在一些不知道是否有血液病的人的血液中检测到。我们分析了来自17,182人外周血细胞DNA的全外显子组测序数据，这些人未被选择为血液学表型。我们通过鉴定血液学癌症中反复突变的160个基因中先前表征的单核苷酸变异和小插入或缺失来寻找体细胞突变。分析突变的存在与血液学表型、生存和心血管事件的关系。可检测到的体细胞突变在40岁以下的人群中很少见，但随着年龄的增长频率明显上升。在70 ~ 79岁、80 ~ 89岁和90 ~ 108岁人群中，这些克隆突变分别占9.5%（2300人中219人）、11.7%（317人中37人）和18.4%（103人中19人）。大多数变异发生在三个基因：DNMT3A、TET2和ASXL1。体细胞突变的存在与血液癌风险增加（风险比，11.1；95%可信区间[CI]， 3.9至32.6）、全因死亡率增加（风险比，1.4;95% CI， 1.1至1.8）、冠心病发生风险增加（风险比，2.0;95% CI， 1.2至3.4）和缺血性中风（风险比，2.6;95% CI， 1.4至4.8）相关。年龄相关性克隆造血是一种常见疾病，与血液癌风险增加和全因死亡率增加有关，后者可能是由于心血管疾病风险增加。（由美国国立卫生研究院和其他机构资助。）
The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.)