Family-based exome-wide assessment of maternal genetic effects on susceptibility to childhood B-cell acute lymphoblastic leukemia in hispanics.
Family-based exome-wide assessment of maternal genetic effects on susceptibility to childhood B-cell acute lymphoblastic leukemia in hispanics.
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DOI：
10.1002/cncr.30241
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发表时间：
2016-12-01
期刊：
影响因子：
6.2
通讯作者：
Lupo, Philip J.
中科院分区：
文献类型：
--
作者：
Archer, Natalie P.;Perez-Andreu, Virginia;Scheurer, Michael E.;Rabin, Karen R.;Peckham-Gregory, Erin C.;Plon, Sharon E.;Zabriskie, Ryan C.;De Alarcon, Pedro A.;Fernandez, Karen S.;Najera, Cesar R.;Yang, Jun J.;Antillon-Klussmann, Federico;Lupo, Philip J.
关键词：
西班牙裔儿童的急性淋巴细胞白血病（ALL）发病率高于其他种族，但种族差异的遗传基础仍不完全清楚。迄今为止，儿童ALL的全基因组关联研究（GWAS）主要关注遗传效应;然而，母体遗传效应（母体基因型对后代表型发育的作用）也可能在ALL易感性中发挥作用。我们使用Illumina人类外显子组微珠芯片对患有儿童B细胞ALL（B-ALL）的西班牙裔人群进行了一项基于家族的外显子组全关联研究（EXWAS）。我们使用了312个危地马拉和西班牙裔美国家庭的发现队列和152个西班牙裔美国家庭的独立复制队列。经过多重检验校正后，三个母体SNP接近我们的显著性阈值（P<1.0×10−6）：MTL5 rs12365708（RR=2.62，95% CI=1.61-4.27，P=1.8×10−5）; ALKBH 1 rs6494（RR=3.77，95% CI=1.84-7.74，P=3.7×10−5）; NEUROG 3 rs4536103（RR=1.75，95% CI=1.30-2.37，P=1.2×10−4）。虽然效应大小相似，但这些SNP在我们的复制队列中名义上并不显著。在由发现队列和复制队列组成的荟萃分析中，这些SNP在多重比较校正后仍无统计学显著性（rs 12365708：合并RR=2.27，95% CI=1.48-3.50，P=1.99×10−4; rs6494：合并RR=2.31，95% CI=1.38-3.85，P=0.001; rs 4536103：合并RR=1.67，95% CI=1.29-2.16，P=9.23×10−5）。在第一个以家庭为基础的EXWAS研究与儿童ALL相关的母体基因型效应中，我们的结果并没有暗示母体基因型对西班牙裔美国人疾病风险的重要作用;然而，我们确定了三个可能在易感性中发挥适度作用的母体SNP。
Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) than other ethnic groups, but the genetic basis for racial disparities remain incompletely understood. Genome-wide association studies (GWAS) of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of maternal genotype on offspring phenotype development) may also play a role in ALL susceptibility. We conducted a family-based exome-wide association study (EXWAS) of maternal genetic effects among Hispanics with childhood B-cell ALL (B-ALL) using the Illumina Human Exome BeadChip. We used a discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families. Three maternal SNPs approached our threshold for significance, after correction for multiple testing (P<1.0×10−6): MTL5 rs12365708 (RR=2.62, 95% CI=1.61-4.27, P=1.8×10−5); ALKBH1 rs6494 (RR=3.77, 95% CI=1.84-7.74, P=3.7×10−5); NEUROG3 rs4536103 (RR=1.75, 95% CI=1.30-2.37, P=1.2×10−4). While effect sizes were similar, these SNPs were not nominally significant in our replication cohort. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not statistically significant after correction for multiple comparisons (rs12365708: pooled RR=2.27, 95% CI=1.48-3.50, P=1.99×10−4; rs6494: pooled RR=2.31, 95% CI=1.38-3.85, P=0.001; rs4536103: pooled RR=1.67, 95% CI=1.29-2.16, P=9.23×10−5). In the first family-based EXWAS to investigate maternal genotype effects associated with childhood ALL, our results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, we identified three maternal SNPs that may play a modest role in susceptibility.
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