PDF(Pubmed)
Abstract：
Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and <0.5% in European populations. This risk allele was positively associated with Indigenous American ancestry, showed evidence of selection in human history, and was associated with reduced IKZF1 expression. We identified a putative causal variant in a downstream enhancer that is most active in pro-B cells and interacts with the IKZF1 promoter. This variant disrupts IKZF1 autoregulation at this enhancer and results in reduced enhancer activity in B cell progenitors. Our study reveals a genetic basis for the increased ALL risk in Hispanic/Latino children.
摘要：
与其他种族/族裔群体相比，西班牙裔/拉丁裔儿童在美国患急性淋巴细胞白血病（ALL）的风险最高。然而，这一点的基础仍然没有完全理解。通过遗传精细作图分析，我们在自我报告的西班牙裔/拉丁裔个体中发现了一个新的独立的儿童ALL风险信号，但不是非西班牙裔白人，效应大小为1.44（95%置信区间=1.33-1.55），西班牙裔/拉丁裔人群的风险等位基因频率为18%，欧洲人群<0.5%。这个风险等位基因与美国土著血统呈正相关，显示了人类历史上选择的证据，与IKZF1表达减少有关。我们在下游增强子中鉴定了推定的因果变体，该变体在pro-B细胞中最活跃并与IKZF1启动子相互作用。该变体破坏该增强子处的IKZF1自动调节,并导致B细胞祖细胞中增强子活性降低。我们的研究揭示了西班牙裔/拉丁裔儿童ALL风险增加的遗传基础。
