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.

项目摘要多发性骨髓瘤（MM）是一种无法治愈的浆细胞恶性肿瘤，存活率为50％。 MM是领导者非洲裔美国人的血液学癌症，被诊断为白人的2-3倍。导致这种差异的因素尚不清楚，但遗传学和免疫失调却可以发挥作用关键角色。该提案的科学目标是：（1）应用利用综合和创新的方法遗传和转录组数据以阐明有助于这种差异的生物学途径，（2）有助于证据以告知该人群未来的精确健康工作。第一个目标是通过进行与MM敏感性相关的假定因果基因使用基因表达的遗传预测模型开发的全转录组结合研究（TWA） TWA将通过在1813年的情况下通过归纳基因表达曲线来进行来自非裔美国人多发性骨髓瘤研究（AAMMS）和8871个对照，全基因组最大非裔美国人的MM协会研究。下一个目标将集中于白细胞（WBC）特征，这是血液学和免疫相关癌症的重要中间表型。分布和 WBC特征的遗传结构在各个种族之间差异很大，可能有助于重要有关非洲裔美国人的MM风险的信息。 WBC变异和MM的共同遗传基础通过进行：（1）全基因组遗传相关分析和（2）发展的敏感性预测个人遗传的特定WBC概况的遗传评分。遗传评分将应用于AAMMS数据以测试其与MM的关联，以及对WBC预测者的比较分析将从非洲和欧洲血统人群中进行。最后一个研究组件将旨在阐明与MM肿瘤特定特征相关的遗传因素。分析将重点放在检查局部遗传血统对躯体事件的贡献，例如易位和放大在非裔美国人患者中更常见。涉及的遗传机制的作用还将研究基因表达或替代剪接，以检验某些肿瘤特征的假设在非裔美国人中看到的是由于种系对这些过程的遗传作用。该研究计划是由培训计划完成的，该计划基于申请人的癌症优势和遗传流行病学，以发展综合和祖先感知基因组分析的新专业知识，血液学癌症和癌症差异。对非裔美国人的MM病因学的新颖见解将是对于改善该人群中的健康结果至关重要，该结果受到MM的影响不成比例的在遗传学研究中代表。研究和培训计划将为申请人做好成功的准备癌症研究的独立职业，跨学科的重点是风险分层和癌症控制。