%0 Journal Article
%T A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children.
%A de Smith AJ
%A Wahlster L
%A Jeon S
%A Kachuri L
%A Black S
%A Langie J
%A Cato LD
%A Nakatsuka N
%A Chan TF
%A Xia G
%A Mazumder S
%A Yang W
%A Gazal S
%A Eng C
%A Hu D
%A Burchard EG
%A Ziv E
%A Metayer C
%A Mancuso N
%A Yang JJ
%A Ma X
%A Wiemels JL
%A Yu F
%A Chiang CWK
%A Sankaran VG
%J Cell Genom
%V 4
%N 4
%D 2024 Apr 10
%M 38537633
暂无%R 10.1016/j.xgen.2024.100526
%X 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.