近日，冰岛大学Kari Stefansson等研究人员合作揭示突变条形码定义克隆造血的遗传学和流行病学。相关论文于2023年11月6日在线发表在《自然—遗传学》杂志上。

通过对45510名冰岛和130709名英国生物库参与者进行全基因组测序，并结合突变条形码方法，研究人员发现了16306名克隆性造血（CH）患者。老年参与者的患病率接近50%。吸烟对CH风险的影响呈剂量依赖性。CH与多种吸烟相关疾病有关。与公开发表的说法相反，研究人员没有发现CH与心血管疾病相关的证据。

研究人员提供的证据表明，CH是由髓样肿瘤中常见的突变基因驱动的，并牵涉到几个新的驱动基因。驱动基因突变的存在和性质会改变血液病的风险特征。然而，大多数CH病例都没有已知的驱动基因突变。一项CH全基因组关联研究确定了25个基因位点，其中包括19个以前未在CH中涉及的位点。基因组范围关联研究发现了CD164和TCL1A的剪接、蛋白质和表达定量性状位点。

据悉，当相当大比例的成熟血细胞来自单一造血干细胞系时，就会出现CH。

附：英文原文

Title: Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis

Author: Stacey, Simon N., Zink, Florian, Halldorsson, Gisli H., Stefansdottir, Lilja, Gudjonsson, Sigurjon A., Einarsson, Gudmundur, Hjrleifsson, Grimur, Eiriksdottir, Thjodbjorg, Helgadottir, Anna, Bjrnsdottir, Gyda, Thorgeirsson, Thorgeir E., Olafsdottir, Thorunn A., Jonsdottir, Ingileif, Gretarsdottir, Solveig, Tragante, Vinicius, Magnusson, Magnus K., Jonsson, Hakon, Gudmundsson, Julius, Olafsson, Sigurgeir, Holm, Hilma, Gudbjartsson, Daniel F., Sulem, Patrick, Helgason, Agnar, Thorsteinsdottir, Unnur, Tryggvadottir, Laufey, Rafnar, Thorunn, Melsted, Pall, Ulfarsson, Magnus ., Vidarsson, Brynjar, Thorleifsson, Gudmar, Stefansson, Kari

Issue&Volume: 2023-11-06

Abstract: Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A. A barcode-based approach applied to UK Biobank and an Icelandic cohort identifies drivers of clonal hematopoiesis (CH) and finds associations between CH and multiple diseases. Genome-wide association analyses identify 25 loci associated with CH susceptibility.

DOI: 10.1038/s41588-023-01555-z

Source: https://www.nature.com/articles/s41588-023-01555-z