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Genome-wide association study on 13 167 individuals identifies regulators of blood CD34+cell levels.
Blood ( IF 20.3 ) Pub Date : 2022-03-17 , DOI: 10.1182/blood.2021013220
Aitzkoa Lopez de Lapuente Portilla 1, 2 , Ludvig Ekdahl 1, 2 , Caterina Cafaro 1, 2 , Zain Ali 1, 2 , Natsumi Miharada 1, 2 , Gudmar Thorleifsson 3 , Kristijonas Žemaitis 1, 2 , Antton Lamarca Arrizabalaga 1, 2 , Malte Thodberg 1, 2 , Maroulio Pertesi 1, 2 , Parashar Dhapola 1, 2 , Erik Bao 4, 5, 6 , Abhishek Niroula 1, 2, 6 , Divya Bali 1, 2 , Gudmundur Norddahl 3 , Nerea Ugidos Damboriena 1, 2 , Vijay G Sankaran 4, 5, 6 , Göran Karlsson 1, 2 , Unnur Thorsteinsdottir 3 , Jonas Larsson 1, 2 , Kari Stefansson 3 , Björn Nilsson 1, 2, 6
Affiliation  

Stem cell transplantation is a cornerstone in the treatment of blood malignancies. The most common method to harvest stem cells for transplantation is by leukapheresis, requiring mobilization of CD34+ hematopoietic stem and progenitor cells (HSPCs) from the bone marrow into the blood. Identifying the genetic factors that control blood CD34+ cell levels could reveal new drug targets for HSPC mobilization. Here we report the first large-scale, genome-wide association study on blood CD34+ cell levels. Across 13 167 individuals, we identify 9 significant and 2 suggestive associations, accounted for by 8 loci (PPM1H, CXCR4, ENO1-RERE, ITGA9, ARHGAP45, CEBPA, TERT, and MYC). Notably, 4 of the identified associations map to CXCR4, showing that bona fide regulators of blood CD34+ cell levels can be identified through genetic variation. Further, the most significant association maps to PPM1H, encoding a serine/threonine phosphatase never previously implicated in HSPC biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. Through functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates an MYB transcription factor-binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, PPM1H knockdown increases the proportion of CD34+ and CD34+90+ cells in cord blood assays. Our results provide the first large-scale analysis of the genetic architecture of blood CD34+ cell levels and warrant further investigation of PPM1H as a potential inhibition target for stem cell mobilization.

中文翻译:

对 13 167 名个体进行的全基因组关联研究确定了血液 CD34+ 细胞水平的调节因子。

干细胞移植是治疗血液恶性肿瘤的基石。采集用于移植的干细胞的最常见方法是白细胞分离术,需要将骨髓中的 CD34+ 造血干细胞和祖细胞 (HSPC) 动员到血液中。识别控制血液 CD34+ 细胞水平的遗传因素可以揭示 HSPC 动员的新药物靶点。在这里,我们报告了第一个关于血液 CD34+ 细胞水平的大规模、全基因组关联研究。在 13 167 名个体中,我们确定了 9 个显着关联和 2 个暗示关联,由 8 个位点(PPM1H、CXCR4、ENO1-RERE、ITGA9、ARHGAP45、CEBPA、TERT 和 MYC)解释。值得注意的是,其中 4 个已识别的关联映射到 CXCR4,表明可以通过遗传变异来识别血液 CD34+ 细胞水平的真正调节因子。更远,最重要的关联映射到 PPM1H,编码一种以前从未与 HSPC 生物学相关的丝氨酸/苏氨酸磷酸酶。PPM1H 在 HSPC 中表达,赋予较高血液 CD34+ 细胞水平的等位基因会下调 PPM1H。通过功能精细定位,我们发现这种下调是由变体 rs772557-A 引起的,该变体消除了 PPM1H 内含子 1 中的 MYB 转录因子结合位点,该位点在特定 HSPC 亚群(包括造血干细胞)中活跃,并与造血干细胞相互作用。通过染色质环启动子。此外,PPM1H 敲低增加了脐带血检测中 CD34+ 和 CD34+90+ 细胞的比例。
更新日期:2022-01-10
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