Cato Liam D, Li Rick, Lu Henry Y, Yu Fulong, Wissman Mariel, Mkumbe Baraka S, Ekwattanakit Supachai, Deelen Patrick, Mwita Liberata, Sangeda Raphael, Suksangpleng Thidarat, Riolueang Suchada, Bronson Paola G, Paul Dirk S, Kawabata Emily, Astle William J, Aguet Francois, Ardlie Kristin, de Lapuente Portilla Aitzkoa Lopez, Kang Guolian, Zhang Yingze, Nouraie Seyed Mehdi, Gordeuk Victor R, Gladwin Mark T, Garrett Melanie E, Ashley-Koch Allison, Telen Marilyn J, Custer Brian, Kelly Shannon, Dinardo Carla Luana, Sabino Ester C, Loureiro Paula, Carneiro-Proietti Anna Bárbara, Maximo Cláudia, Méndez Adriana, Hammerer-Lercher Angelika, Sheehan Vivien A, Weiss Mitchell J, Franke Lude, Nilsson Björn, Butterworth Adam S, Viprakasit Vip, Nkya Siana, Sankaran Vijay G
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
medRxiv. 2023 Mar 28:2023.03.24.23287659. doi: 10.1101/2023.03.24.23287659.
Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation. Here, we have conducted a multi-ancestry genome-wide association study of 28,279 individuals from several cohorts spanning 5 continents to define the architecture of human genetic variation impacting HbF. We have identified a total of 178 conditionally independent genome-wide significant or suggestive variants across 14 genomic windows. Importantly, these new data enable us to better define the mechanisms by which HbF switching occurs . We conduct targeted perturbations to define BACH2 as a new genetically-nominated regulator of hemoglobin switching. We define putative causal variants and underlying mechanisms at the well-studied and loci, illuminating the complex variant-driven regulation present at these loci. We additionally show how rare large-effect deletions in the locus can interact with polygenic variation to influence HbF levels. Our study paves the way for the next generation of therapies to more effectively induce HbF in sickle cell disease and β-thalassemia.
人类遗传变异已促成了几种胎儿血红蛋白向成人血红蛋白转换的关键调节因子的鉴定，包括BCL11A，从而带来了治疗进展。然而，尽管已取得进展，但在全面解释遗传变异如何影响胎儿血红蛋白（HbF）基因调控的整体机制方面，仍缺乏进一步的深入见解。在此，我们对来自五大洲多个队列的28279名个体进行了多血统全基因组关联研究，以确定影响HbF的人类遗传变异结构。我们在14个基因组窗口中总共鉴定出178个条件独立的全基因组显著或提示性变异。重要的是，这些新数据使我们能够更好地确定HbF转换发生的机制。我们进行了靶向扰动，将BACH2定义为一种新的血红蛋白转换的基因提名调节因子。我们在研究充分的和位点确定了推定的因果变异和潜在机制，阐明了这些位点存在的复杂的变异驱动调控。我们还展示了位点中罕见的大效应缺失如何与多基因变异相互作用以影响HbF水平。我们的研究为下一代更有效地在镰状细胞病和β地中海贫血中诱导HbF的疗法铺平了道路。
