Comprehensive Investigation of Multiple Myeloma Genetic Susceptibility in African Americans

非裔美国人多发性骨髓瘤遗传易感性的综合调查

基本信息

批准号：
10654122
负责人：
Mirlinda Kachuri
金额：
$ 24.9万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654122
关键词：
Accounting Affect African African American African American population African ancestry Alternative Splicing Awareness Biological Biology Blood Cells Bone Marrow Cancer Control Cancer Research Project Cessation of life Clinical Clonal Expansion Complement Data Development Diagnosis Environmental Exposure Epidemiology Ethnic Origin Etiology European Event Frequencies Future Gene Expression Genes Genetic Genetic Determinism Genetic Predisposition to Disease Genetic Research Genetic Variation Genetic study Genomics Goals Health Hematologic Neoplasms Hematology Immune Incidence Individual Inherited Investigation Leukocytes Malignant Neoplasms Maps Mendelian randomization Methods Multiomic Data Multiple Myeloma Mutation Outcome Participant Pathway interactions Patients Phenotype Plasma Cells Play Population Positioning Attribute Precision Health Predisposition Process Quantitative Trait Loci RNA Splicing Research Research Training Risk Role Spliced Genes Survival Rate Testing Time Training Underrepresented Populations Variant White Blood Cell Count procedure Work anticancer research base cancer epidemiology cancer health disparity career causal variant comparative design experience gene expression variation genetic architecture genetic epidemiology genetic variant genome wide association study genome-wide health equity high risk improved innovation insight novel polygenic risk score predictive modeling programs racial and ethnic racial and ethnic disparities risk stratification risk variant trait transcriptome transcriptomics tumor tumor heterogeneity

项目摘要

PROJECT SUMMARY Multiple myeloma (MM) is an incurable plasma cell malignancy with a 50% survival rate. MM is the leading hematological cancer in African Americans, who are diagnosed 2-3 times more commonly than whites. The factors contributing to this disparity remain unclear, but genetics and immune dysregulation are believed to play a key role. The scientific goals of this proposal are: (1) to apply integrative and innovative methods that leverage genetic and transcriptomic data to elucidate biological pathways contributing to this disparity and (2) to contribute evidence to inform future precision health efforts in this population. The first objective will be to identify putative causal genes associated with MM susceptibility by conducting a transcriptome-wide association study (TWAS), using genetic prediction models of gene expression developed specifically in African Americans. TWAS will be performed by imputing gene expression profiles in 1813 cases from the African American Multiple Myeloma Study (AAMMS) and 8871 controls, the largest genome-wide association study of MM in African Americans. The next objective will focus on white blood cell (WBC) traits, which are important intermediate phenotypes for hematologic and immune-related cancers. The distribution and genetic architecture of WBC traits varies substantially across ethnicities and may contribute important information for deciphering MM risk in African Americans. The shared genetic basis of WBC variation and MM susceptibility will be examined by conducting: (1) genome-wide genetic correlation analyses and (2) developing genetic scores for predicting an individual’s inherited predisposition to a specific WBC profile. Genetic scores will be applied to AAMMS data to test their association with MM, and comparative analyses of WBC-predictors from African and European ancestry populations will be conducted. The last research component will aim to elucidate genetic factors that are associated with specific features of MM tumors. Analyses will focus on examining the contribution of local genetic ancestry to somatic events, such as translocations and amplifications that are more commonly observed in African American patients. The role of genetic mechanisms involved in gene expression or alternative splicing will also be investigated, to test the hypothesis that some tumor features seen in African Americans are due to germline genetic effects on these processes. This research plan is complemented by a training plan that builds on the applicant’s strengths in cancer and genetic epidemiology to develop new expertise in integrative and ancestry-aware genomic analyses, hematological cancer, and cancer disparities. Novel insights into MM etiology in African Americans will be important for improving health outcomes in this population that is disproportionately affected by MM, yet under- represented in genetics studies. The research and training plan will prepare the applicant for a successful independent career in cancer research with an interdisciplinary focus on risk stratification and cancer control.

项目概要多发性骨髓瘤 (MM) 是一种无法治愈的浆细胞恶性肿瘤，其存活率为 50%。非裔美国人患血液癌的几率是白人的 2-3 倍。造成这种差异的因素尚不清楚，但据信遗传和免疫失调发挥了作用该提案的科学目标是：（1）应用综合和创新方法。遗传和转录组数据来阐明造成这种差异的生物学途径，并且（2）有助于为该人群未来精准健康工作提供信息的证据。第一个目标是通过进行以下研究来确定与 MM 易感性相关的推定致病基因：一项全转录组关联研究（TWAS），使用开发的基因表达的遗传预测模型特别是在非裔美国人中，将通过估算 1813 个病例的基因表达谱来进行 TWAS。来自非裔美国人多发性骨髓瘤研究 (AAMMS) 和 8871 个对照，这是最大的全基因组研究非裔美国人 MM 关联研究的下一个目标将集中于白细胞 (WBC) 特征，它们是血液学和免疫相关癌症的重要中间表型。白细胞特征的遗传结构在不同种族之间差异很大，并且可能具有重要作用解读非裔美国人 MM 风险的信息 WBC 变异和 MM 的共同遗传基础。将通过以下方式检查易感性：（1）全基因组遗传相关性分析和（2）开发用于预测个体对特定白细胞概况的遗传倾向的遗传评分。将应用于 AAMMS 数据以测试它们与 MM 的关联，以及 WBC 预测因子的比较分析最后一个研究部分将针对非洲和欧洲血统人群进行。阐明与 MM 肿瘤特定特征相关的遗传因素。检查当地遗传祖先对体细胞事件的贡献，例如易位和扩增在非洲裔美国患者中更常见，其中涉及遗传机制的作用。还将研究基因表达或选择性剪接，以检验某些肿瘤特征的假设在非裔美国人中看到的现象是由于种系遗传对这些过程的影响。该研究计划辅以基于申请人在癌症方面的优势的培训计划和遗传流行病学，以开发综合和祖先意识基因组分析的新专业知识，血液学癌症和癌症差异将成为非裔美国人 MM 病因学的新见解。对于改善该人群的健康结果非常重要，该人群受 MM 的影响尤为严重，但尚未得到充分重视研究和培训计划将为申请人的成功做好准备。癌症研究的独立职业，跨学科重点关注风险分层和癌症控制。