BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.
BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.
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DOI：
10.1002/ijc.31622
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发表时间：
2018-12-01
影响因子：
6.4
通讯作者：
Wiemels JL
中科院分区：
文献类型：
--
作者：
de Smith AJ;Walsh KM;Francis SS;Zhang C;Hansen HM;Smirnov I;Morimoto L;Whitehead TP;Kang A;Shao X;Barcellos LF;McKean-Cowdin R;Zhang L;Fu C;Wang R;Yu H;Hoh J;Dewan AT;Metayer C;Ma X;Wiemels JL
儿童急性淋巴细胞白血病（ALL）的全基因组关联研究已经确定了PIP 4K 2A和染色体10p12.31-12.2处BMI 1上游的关联区域。这两个基因座对ALL风险和潜在功能变异的贡献仍有待阐明。我们对来自两项独立加州儿童白血病研究的拉丁裔和非拉丁裔白色ALL病例和对照组以及额外的衰老遗传流行病学研究对照组的染色体10 p12.31 -12.2进行了单核苷酸多态性（SNP）插补。使用逻辑回归进行种族分层关联分析，荟萃分析包括3133例病例（1949例拉丁裔，1184例非拉丁裔白色）和12,135例对照（8584例拉丁裔，3551例非拉丁裔白色）。SNP关联在BMI 1和PIP 4K 2A两者上被鉴定。在调整前导PIP 4K 2A SNP后，全基因组显著相关性仍然存在于BMI 1，反之亦然（Pmeta<10−10），支持独立效应。在两个峰值处，主要SNP因种族而异。我们寻找与混血美国人中的主要拉丁裔SNP和欧洲人中的主要非拉丁裔白色SNP紧密连锁不平衡的功能变体。这一发现精确定位了位于BMI 1上游的rs 11591377（Pmeta=2.1×10−10），位于BMI 1的造血干细胞增强子内，并且使用来自SNP杂合子的ChIP-Seq数据的二项式检验显示风险等位基因与MYBL 2（P=1.73×10−5）和p300（P=1.55×10−3）转录因子显著优先结合。在PIP 4K 2A中，我们鉴定了rs 4748812（Pmeta=1.3×10−15），它改变了RUNX 1结合基序，并证明了PIP 4K 2A启动子的染色体环。在多种族ALL GWAS中精细定位染色体10 p12证实了独立的关联，并确定了BMI 1上游和PIP 4K 2A的推定功能变体。
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 3133 cases (1949 Latino, 1184 non-Latino white) and 12,135 controls (8584 Latino, 3551 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 (Pmeta<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 (Pmeta=2.1×10−10) 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=1.73×10−5) and p300 (P=1.55×10−3) transcription factors using binomial tests on ChIP-Seq data from a SNP heterozygote. At PIP4K2A, we identified rs4748812 (Pmeta=1.3×10−15), 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.
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DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Heinz S;Romanoski CE;Benner C;Glass CK
通讯作者：
Glass CK
影响因子：
64.8
作者：
Mullighan, Charles G.;Goorha, Salil;Downing, James R.
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10.1073/pnas.1315464111
发表时间：
2014-02-25
影响因子：
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作者：
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Reddy, E. Premkumar
影响因子：
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影响因子：
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通讯作者：
Stocking, Carol