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）中最常见的癌症类型， 自1975年以来，美国儿童ALL的发病率持续增加。全基因 关联研究（GWAS）已经确定了几个基因中的常见变异，这些基因与 包括ARID 5 B、IKZF 1和CEBPE。然而，可能还有其他 目前GWAS可能无法检测到的导致ALL遗传性的变异。那里 越来越多的证据表明，稳定的和可塑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。microRNA（miRNA）是一种表观遗传因子， 转录调节许多生物学机制，如细胞凋亡、适应性和先天免疫。 microRNA调控最近成为一种重要的，但尚未开发的机制，可以改变 与癌发生有关的多个基因的表达。我们假设miRNA修饰是 与所有风险相关。此外，我们假设miRNAs中的变异体和 相应的miRNA结合位点有助于ALL的易感性， 这两个区域中的变异可能以非累加方式导致ALL风险。为了验证这些假设， 我们将对来自两个大型儿童ALL GWAS的基因分型数据进行广泛的生物信息学分析， 在2016年完成，在整个发现和复制过程中有超过4500个案例和近5000个控件 数据集主要由西班牙裔/拉丁裔和白人组成，但也包含亚洲和非洲的主题- 美国血统。这些受试者已经进行了超过70万个单核苷酸的基因分型， 基因组中的多态性增加观察到miRNAs内多态性的机会， 为了增加在不同基因分型平台上进行基因分型的受试者之间的可比性，我们将进行整个 在分析之前进行基因组插补。我们将首先鉴定miRNA编码区和miRNA 与ALL风险相关的结合位点。然后我们将采取基于基因的方法来识别罕见的 在miRNA编码区和miRNA结合位点中及其周围的变异（次要等位基因频率小于1%） 与ALL风险相关的风险。最后，我们将研究是否变异之间的相互作用， miRNA编码区及其特异性结合位点与相关靶基因在ALL中的作用 易感性这些目的是研究miRNA编码区遗传变异的作用， 在全基因组范围内进行的miRNA结合位点的研究有望为miRNA的作用提供新的见解 在儿童ALL的病因学中，由于不断增加的 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.