小柯机器人

英国剑桥大学George S. Vassiliou等研究人员合作对200,453名个体进行全基因组分析，为克隆性造血的原因和后果提供新见解。相关论文于2022年7月14日在线发表在《自然—遗传学》杂志上。

研究人员分析了来自200,453名英国生物库参与者的遗传数据，用于绘制遗传性易感性的图谱，将欧洲血统人群中与克隆造血（CH）相关的种系数量从4个增加到14个。新位点的基因与DNA损伤修复（PARP1、ATM、CHEK2）、造血干细胞迁移/归巢（CD164）和骨髓肿瘤发生（SETBP1）有关。一些关联是CH亚型特异性的，包括TCL1A和CD164的变体与DNMT3A-和TET2-突变的CH（两个最常见的CH亚型）有相反的关联，提出这两个基因座在CH发展中的关键作用。

孟德尔随机化分析显示，吸烟和较长的白细胞端粒长度是CH的因果风险因素，CH的遗传易感性增加了骨髓增生性肿瘤、非血液学恶性肿瘤、心房颤动和血液表观遗传学衰老的风险。

据悉，CH，即由体细胞驱动突变驱动的造血干细胞及其后代的克隆性扩张，影响到三分之一以上的人，但人们对其了解仍然不多。

附：英文原文

Title: Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis

Author: Kar, Siddhartha P., Quiros, Pedro M., Gu, Muxin, Jiang, Tao, Mitchell, Jonathan, Langdon, Ryan, Iyer, Vivek, Barcena, Clea, Vijayabaskar, M. S., Fabre, Margarete A., Carter, Paul, Petrovski, Slav, Burgess, Stephen, Vassiliou, George S.

Issue&Volume: 2022-07-14

Abstract: Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing. Analysis of whole-exome sequencing data from 200,453 UK Biobank participants identifies loci associated with clonal hematopoiesis and highlights causal links between clonal hematopoiesis and other traits.

DOI: 10.1038/s41588-022-01121-z

Source: https://www.nature.com/articles/s41588-022-01121-z

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