美国再生基因中心Eric Jorgenson团队近期取得重要工作进展，他们研究分析了克隆造血表型的常见和罕见变异关联。相关研究成果2022年11月30日在线发表于《自然》杂志上。

据介绍，克隆造血涉及某些血细胞谱系的扩张，并与衰老和不良健康结果相关。

研究人员使用628388个个体的外显子序列数据来鉴定40208个具有不确定潜能的克隆性造血（CHIP）携带者。通过全基因组和外显子组关联分析，研究人员确定了24个基因座(其中21个是新发现的)，在这些基因座中，种系遗传变异影响CHIP易感性，包括淋巴细胞抗原编码基因LY75的错义变异，它与CHIP发病率降低相关。研究人员还发现了与克隆造血和端粒长度相关的新的罕见变异。对英国生物银行（UKB）5041项健康特征的分析发现，CHIP与严重新冠肺炎发生、心血管疾病、血液学特征、恶性肿瘤、吸烟、肥胖、感染和全因死亡率之间存在关系。纵向和孟德尔随机化分析表明，CHIP与实体癌相关，包括非黑色素瘤皮肤癌和肺癌，并且与DNMT3A相关的CHIP与随后的髓系白血病而非淋巴性白血病的发展相关。

此外，与之前对5万个UKB外显子的发现相反，研究人员在完整样本中的结果不支持IL-6抑制在降低CHIP携带者心血管疾病风险中的作用。这一发现表明，CHIP代表了一组复杂的异质表型，具有共同和独特的种系遗传基因和不同的临床意义。

附：英文原文

Title: Common and rare variant associations with clonal haematopoiesis phenotypes

Author: Kessler, Michael D., Damask, Amy, OKeeffe, Sean, Banerjee, Nilanjana, Li, Dadong, Watanabe, Kyoko, Marketta, Anthony, Van Meter, Michael, Semrau, Stefan, Horowitz, Julie, Tang, Jing, Kosmicki, Jack A., Rajagopal, Veera M., Zou, Yuxin, Houvras, Yariv, Ghosh, Arkopravo, Gillies, Christopher, Mbatchou, Joelle, White, Ryan R., Verweij, Niek, Bovijn, Jonas, Parikshak, Neelroop N., LeBlanc, Michelle G., Jones, Marcus, Glass, David J., Lotta, Luca A., Cantor, Michael N., Atwal, Gurinder S., Locke, Adam E., Ferreira, Manuel A. R., Deering, Raquel, Paulding, Charles, Shuldiner, Alan R., Thurston, Gavin, Ferrando, Adolfo A., Salerno, Will, Reid, Jeffrey G., Overton, John D., Marchini, Jonathan, Kang, Hyun M., Baras, Aris, Abecasis, Gonalo R., Jorgenson, Eric

Issue&Volume: 2022-11-30

Abstract: Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes1,2,3,4,5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000UKB exomes6, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

DOI: 10.1038/s41586-022-05448-9

Source: https://www.nature.com/articles/s41586-022-05448-9