Identification of microRNA variants associated with acute lymphoblastic leukemia

急性淋巴细胞白血病(ALL)是儿童(0-14岁)最常见的癌症类型， 自1975年以来，美国儿童ALL的发病率持续上升。全基因组 关联研究已经在几个显著相关的基因中发现了常见的变异 有发展包括ARID5B、IKZF1和CEBPE在内的所有疾病的风险。然而，可能还有其他 可能没有能力检测到导致当前所有GWA的遗传性的变种。那里 越来越多的证据表明，稳定的和可塑性的表观遗传修饰也可能发挥重要作用 包括白血病在内的许多癌症的遗传性。微小核糖核酸(MiRNA)，一种表观遗传因子，后 转录调控多种生物机制，如细胞凋亡、获得性免疫和先天免疫。 最近，microRNA调控已成为一种重要的、但尚未被探索的、可以改变的机制 多种基因的表达与肿瘤的发生有关。我们假设miRNA的修饰是 可遗传的，与所有风险相关的。此外，我们假设miRNA中的变体和miRNA中的变体 对应的miRNA结合位点有助于ALL的易感性以及 这两个地区的变异可能以非累加的方式导致所有风险。为了检验这些假设， 我们将对两个大型儿童急性淋巴细胞白血病的基因分型数据进行广泛的生物信息学分析。 于2016年完成，在发现和复制领域拥有超过4500个案例和近5000个控制 数据集主要由拉美裔/拉丁裔和白人组成，但也包含亚洲和非洲的主题- 美国血统。这些受试者已经对70多万个单核苷酸进行了基因分型 基因组中的多态现象。增加观察到miRNAs内多态的机会，以及 为了增加在不同基因分型平台上分型的受试者之间的可比性，我们将进行 分析前的基因组拼接。我们将首先确定miRNA编码区和miRNA内的变体 与ALL风险相关的结合位点。然后，我们将采用基于基因的方法来识别稀有 MiRNA编码区和miRNA结合位点及其周围的变异(次要等位基因频率低于1%) 总体上与所有人的风险相关。最后，我们将研究 MiRNA编码区及其特异的miRNA结合位点和相关的靶基因对ALL有贡献 敏感度。这些目的是研究遗传遗传变异在miRNA编码区和 在全基因组范围内完成的miRNA结合位点有望对miRNAs的作用提供新的见解 在儿童ALL的病因学方面，一个具有公共卫生意义的研究领域不断增多 发病率。

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children (age 0-14 years), and the incidence of childhood ALL has continuously increased in the United States since 1975. Genome-wide association studies (GWAS) have identified common variants in several genes that are significantly associated with the risk of developing ALL including ARID5B, IKZF1 and CEBPE. However, there are likely additional variants contributing to the heritability of ALL that current GWAS may not have been powered to detect. There is mounting evidence to suggest that stable and plastic epigenetic modification may also play an essential role in heritability of many cancers including leukemia. MicroRNA (miRNA), one epigenetic factor, post- transcriptionally regulates many biological mechanisms, such as apoptosis, adaptive and innate immunity. MicroRNA regulation has recently emerged as an important, yet under-explored, mechanism that can change the expression of multiple genes implicated in carcinogenesis. We hypothesize that miRNA modification is heritable and associated with ALL risk. Further, we postulate that variants within miRNAs and variants in corresponding miRNA binding sites contribute to the susceptibility of ALL and that interactions between variants in these two regions may contribute to ALL risk in a non-additive manner. To test these hypotheses, we will conduct extensive bioinformatics analyses of genotyping data from two large GWAS of childhood ALL completed in 2016, with more than 4500 cases and nearly 5000 controls across the Discovery and Replication datasets comprised primarily of Hispanics/Latinos and Whites, but also contain subjects of Asian and African- American ancestry. These subjects have been genotyped for more than 700,000 single-nucleotide polymorphisms across the genome. To increase the chance of observing polymorphisms within miRNAs, and to increase comparability between subjects genotyped on different genotyping platforms, we will conduct whole genome imputation prior to analysis. We will first identify variants within miRNA coding regions and miRNA binding sites that are associated with risk of ALL. We will then take a gene-based approach to identify rare variants (minor allele frequency less than 1%) in and around miRNA coding regions and miRNA binding sites that are associated with risk of ALL in aggregate. Finally, we will investigate if interactions between variants in miRNA coding regions and their specific miRNA biding sites and associated target gene contribute to ALL susceptibility. These aims investigating the role of inherited genetic variation in miRNA coding regions and miRNA binding sites done on a genome-wide scale will hopefully provide new insights into the role of miRNAs in the etiology of childhood ALL, a research area of public health significance given the continuously increasing incidence.