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 González Burchard, Elad Ziv, Catherine Metayer, Nicholas Mancuso, Jun J Yang, Xiaomei Ma, Joseph L Wiemels, Fulong Yu, Charleston W K Chiang, Vijay G Sankaran
{"title":"IKZF1的非编码调控变体会增加西班牙裔/拉美裔儿童患急性淋巴细胞白血病的风险。","authors":"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 González Burchard, Elad Ziv, Catherine Metayer, Nicholas Mancuso, Jun J Yang, Xiaomei Ma, Joseph L Wiemels, Fulong Yu, Charleston W K Chiang, Vijay G Sankaran","doi":"10.1016/j.xgen.2024.100526","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1000,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019360/pdf/","citationCount":"0","resultStr":"{\"title\":\"A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children.\",\"authors\":\"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 González Burchard, Elad Ziv, Catherine Metayer, Nicholas Mancuso, Jun J Yang, Xiaomei Ma, Joseph L Wiemels, Fulong Yu, Charleston W K Chiang, Vijay G Sankaran\",\"doi\":\"10.1016/j.xgen.2024.100526\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":72539,\"journal\":{\"name\":\"Cell genomics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":11.1000,\"publicationDate\":\"2024-04-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019360/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell genomics\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.xgen.2024.100526\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/3/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell genomics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.xgen.2024.100526","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children.
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.