PDE4B and pharmacoethnicity of childhood leukemia

描述（由申请人提供）：虽然儿童急性淋巴细胞白血病（ALL）的治愈率接近85%，但并非所有儿童都能从这一令人印象深刻的进展中平等受益。不同种族的ALL结局存在显著差异，西班牙裔和黑人的复发率显著较高。对ALL治疗反应的种族差异的根本原因在很大程度上是难以捉摸的，而遗传和环境因素可能都很重要。初步结果/依据：在一项对2,534名新诊断的ALL儿童的初步研究中，我们进行了全基因组关联分析，以系统地识别导致ALL结局种族差异的种系遗传变异。首先，我们证明了在不同的治疗方案中，基因定义的美洲印第安人血统会增加西班牙裔美国人的复发率。随后的全基因组扫描鉴定了PDE 4 B基因中的一簇遗传变异，其与白血病复发风险的关联最强（N= 2，534，P=2.6W10-6）。重要的是，PDE 4 B SNP的风险等位基因在西班牙裔中比白人多1.5倍，这导致了ALL复发风险的祖先相关差异。PDE 4 B的遗传变异也与ALL的其他药物反应表型（微小残留病、糖皮质激素反应和毒性）相关。研究目的：鉴于有令人信服的证据支持PDE 4 B在ALL药物遗传学中的重要性，本申请的目的是：1）系统地鉴定PDE 4 B基因的遗传变异，并表征其对ALL治疗反应种族差异的贡献，2）建立实验室模型，以机械表征PDE 4 B等位基因变体及其在抗白血病药物反应种族差异中的作用。成果：这些研究的成功完成将坚定地确立PDE 4 B在ALL结局种族差异中的重要性，并鼓励开发PDE 4 B拮抗剂作为克服白血病耐药性的一种手段。我们的长期目标是利用基因组变异如何解释ALL结局中的种族差异的知识，以便我们可以通过药物基因组学测试实施个性化药物，以改善所有种族ALL儿童的生存率。 公共卫生相关性：对于某些癌症，治愈率存在很大的种族差异。采用药物遗传学方法，我们建议确定PDE 4 B基因中的遗传变异对儿童白血病治愈率种族差异的贡献，以及这些基因变异如何影响抗白血病药物反应的种族差异。从长远来看，我们的目标是消除儿童白血病治愈率的种族/民族差异。

DESCRIPTION (provided by applicant): While the cure rates of childhood acute lymphoblastic leukemia (ALL) are approaching 85%, not all children benefit equally from this impressive progress. There are substantial differences in ALL outcome by race, with significantly higher relapse rates in Hispanics and blacks. The underlying causes of racial disparities in response to ALL therapy are largely elusive, while genetic and environmental factors may both be important. Preliminary results/rationale: In a preliminary study of 2,534 children with newly diagnosed ALL, we performed genome-wide association analysis to systematically identify germline genetic variations responsible for racial differences in ALL outcome. First, we demonstrated that genetically defined American Indian ancestry underlay the elevated rate of relapse in Hispanics across various treatment protocols. A subsequent genome- wide scan identified a cluster of genetic variations in the PDE4B gene with the strongest association with leukemia relapse risk (N=2,534, P=2.6W10-6). Importantly, the risk allele at the PDE4B SNP was 1.5 times more common in Hispanics than whites, contributing to the ancestry-related differences in ALL relapse risk. Genetic variation in PDE4B also exhibited association with other drug response phenotypes in ALL (minimal residual disease, glucocorticoid response and toxicity). Research objectives: Given the compelling evidence in support of the importance of PDE4B in ALL pharmacogenetics, the objectives of this application are to 1) systematically identify genetic variations in the PDE4B gene and characterize their contribution to racial differences in ALL treatment response, and 2) to establish laboratory models to mechanistically characterize PDE4B allelic variants and their role in racial differences in antileukemic drug response. Outcomes: Successful completion of these studies will firmly establish the importance of PDE4B in racial disparities in ALL outcome and encourage the development of PDE4B antagonists as a means of overcoming drug resistance in leukemia. Our long-term goal is to utilize knowledge on how genomic variation may explain racial disparities in ALL outcomes, so that we can implement personalized medicine via pharmacogenomics testing to improve the survival of children of all races with ALL. PUBLIC HEALTH RELEVANCE: For some cancers, there are substantial racial disparities in cure rates. Taking a pharmacogenetics approach, we propose to determine the contribution of genetic variations in the PDE4B gene to racial differences in cure rates for childhood leukemia, and how those gene variations affect racial differences in response to anti- leukemic medications. Long term, we aim to eradicate race/ethnicity differences in cure rates of childhood leukemia.