A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children
Adam J. de Smith, Lara Wahlster, Soyoung Jeon, Linda Kachuri, Susan Black, Jalen Langie, Liam D. Cato, Nathan Nakatsuka, Tsz-Fung Chan, Guangze Xia, Soumyaa Mazumder, Wenjian Yang, Steven Gazal, Celeste Eng, Donglei Hu, Esteban G. Burchard, Elad Ziv, Catherine Metayer, Nicholas Mancuso, Jun J. Yang, Xiaomei Ma, Joseph L. Wiemels, Fulong Yu, Charleston W. K. Chiang, Vijay G. Sankaran
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.