BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia

被引:22
作者
de Smith, Adam J. [1 ,2 ,10 ]
Walsh, Kyle M. [1 ,3 ]
Francis, Stephen S. [4 ]
Zhang, Chenan [1 ,5 ]
Hansen, Helen M. [5 ]
Smirnov, Ivan [5 ]
Morimoto, Libby [6 ]
Whitehead, Todd P. [6 ]
Kang, Alice [6 ]
Shao, Xiaorong [6 ]
Barcellos, Lisa F. [6 ]
McKean-Cowdin, Roberta [2 ]
Zhang, Luoping [6 ]
Fu, Cecilia [7 ]
Wang, Rong [8 ]
Yu, Herbert [9 ]
Hoh, Josephine [8 ]
Dewan, Andrew T. [8 ]
Metayer, Catherine [6 ]
Ma, Xiaomei [8 ]
Wiemels, Joseph L. [1 ,2 ,5 ]
机构
[1] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA
[2] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Ctr Genet Epidemiol, Los Angeles, CA USA
[3] Duke Univ, Dept Neurosurg, Durham, NC USA
[4] Univ Nevada, Sch Community Hlth Sci, Dept Epidemiol, Reno, NV 89557 USA
[5] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA
[6] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA
[7] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA
[8] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA
[9] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA
[10] USC Norris Comprehens Canc Ctr, 1450 Biggy St,NRT 1509H, Los Angeles, CA 90033 USA
基金
美国国家卫生研究院;
关键词
childhood acute lymphoblastic leukemia; genome-wide association study; fine-mapping; BMI1; enhancer element; B-MYB; CELL; EXPRESSION; PROLIFERATION; RISK; IMPUTATION; VARIANTS; COMPLEX; CDKN2A; GENES;
D O I
10.1002/ijc.31622
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (p(meta) < 10(-10)), supporting independent effects. Lead SNPs differed by ethnicity at both peaks. We sought functional variants in tight linkage disequilibrium with both the lead Latino SNP among Admixed Americans and lead non-Latino white SNP among Europeans. This pinpointed rs11591377 (p(meta) = 2.1 x 10(-10)) upstream of BMI1, residing within a hematopoietic stem cell enhancer of BMI1, and which showed significant preferential binding of the risk allele to MYBL2 (p = 1.73 x 10(-5)) and p300 (p = 1.55 x 10(-3)) transcription factors using binomial tests on ChIP-Seq data from a SNP heterozygote. At PIP4K2A, we identified rs4748812 (p(meta) = 1.3 x 10(-15)), which alters a RUNX1 binding motif and demonstrated chromosomal looping to the PIP4K2A promoter. Fine-mapping chromosome 10p12 in a multi-ethnic ALL GWAS confirmed independent associations and identified putative functional variants upstream of BMI1 and at PIP4K2A.
引用
收藏
页码:2647 / 2658
页数:12
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