Epigenetic contribution to the excess risk of MGUS in African Americans

表观遗传对非裔美国人 MGUS 过度风险的影响

基本信息

批准号：
10215787
负责人：
Elizabeth E Brown
金额：
$ 61.63万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-13 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10215787
关键词：
Address Affect African American Age American Antibodies Apoptosis Biological Biological Markers Bone Marrow Cell Proliferation Clinical Clinical Data Complex Cytogenetics DNA DNA Sequence Data Diagnostic Discipline Disease Environmental Exposure Environmental Risk Factor Epidemiology Epigenetic Process Etiology European Evaluation Event Extramedullary Family history of Gene Expression Genes Genetic Genetic Transcription Geography Goals Hematologic Neoplasms Hematopoietic Neoplasms Heritability Incidence Individual Inherited International Investigation Knowledge Leukocytes Lymphoma Malignant Neoplasms Malignant lymphoid neoplasm Maps Messenger RNA Methylation Modeling Modification Monitor Monoclonal gammopathy of uncertain significance Multiple Myeloma Obesity Participant Plasma Cells Play Population Positioning Attribute Predisposition Quantitative Trait Loci Race Resistance Resources Risk Risk Factors Role Sampling Single Nucleotide Polymorphism Site Specificity Testing Time Validation Variant advanced analytics base bead chip bisulfite sequencing case control clinically significant epigenome epigenomics exome functional genomics genome wide association study high risk high risk population improved insight male methylome neoplastic cell peripheral blood sex transcriptome transcriptome sequencing trend

项目摘要

ABSTRACT The goal of this investigation is to characterize the influence of the DNA methylome central to the increased risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) observed in African Americans compared to European Americans. To facilitate an improved understanding of the epigenetic modifications underlying the disparate trends in MGUS risk observed by race, we will address MMDPQ1: What risk factors, singularly or in cooperation, explain the variation in monoclonal gammopathy of undetermined significance (MGUS) incidence among different races? MGUS precedes Multiple Myeloma (MM), which is the most common blood cancer affecting African Americans, characterized by cellular resistance to apoptosis leading to prolonged survival and accumulation of clonally expanded, cytogenetically heterogeneous, antibody producing tumor cells in the bone marrow and extramedullary sites. Risk of MGUS is 2- to 3-fold higher among African Americans compared to European Americans and beyond a few well-established risk factors (race, male sex, obesity, family history of lymphoid malignancy) little is known about the observed disparity in MGUS risk. Although, evidence suggests a germline component, inherited alterations in DNA sequence alone does not explain the disparity. Advances in epigenomics offer new opportunities to characterize the heritable changes in gene activity, or plasticity in germline variation due to past environmental exposures, which could significantly improve our understanding MGUS etiology, differences by ancestry and provide new insight for improved clinical monitoring in high-risk populations. We will test the overarching hypothesis that distinct methylome signatures correlate with the excess risk of MGUS observed in African Americans and that aberrant epigenetic modification influences the disparity in risk by altering target gene expression. Using an epigenome-wide approach, we will capitalize on a unique opportunity to explore differentially methylated positions in DNA obtained from a network of well-characterized, treatment naïve populations of MGUS and MM while taking advantage of recent technological and analytic advances. This project leverages existing partnerships, resources and comprehensive, high-quality clinical data and biospecimens systematically collected in a well-characterized network of treatment-naïve populations, to improve our understanding of the disparate trends in MGUS risk observed by race and to advance a set of biomarkers required to improve efforts to predict and manage MGUS clinical course in high-risk African American populations.

抽象的这项投资的目的是表征DNA甲基组对增加风险增加的影响与非洲裔美国人观察到的不确定意义（MGU）的单克隆性伽马病相比欧洲人。为了促进对依据的表观遗传修饰的改进种族观察到的MGUS风险的不同趋势，我们将介绍MMDPQ1：奇异的风险因素合作，解释不确定意义（MGUS）事件的单克隆伽马病的变化在不同的种族中？ MGU在多发性骨髓瘤（MM）之前，这是最常见的血液癌影响非洲裔美国人，其特征是细胞对细胞凋亡的抗性，导致生存时间延长和克隆膨胀，细胞遗传学异质，抗体产生肿瘤细胞的积累骨髓和外部卸载遗址。非裔美国人的MGU风险比欧洲裔美国人以及几个公认的危险因素（种族，男性，肥胖，家族史淋巴恶性肿瘤）关于MGUS风险的观察到的差异知之甚少。虽然，有证据表明生殖线成分，仅在DNA序列中的遗传改变并不能解释差异。进步表观基因组学提供了新的机会来表征基因活性的可遗传变化或种系可塑性由于过去的环境暴露而导致的变化，这可能会大大改善我们的理解MGU 病因，祖先的差异，为改善高风险人群的临床监测提供了新的见解。我们将测试总体假设，即不同的甲基体特征与MGU的过量风险相关在非洲裔美国人中观察到，异常表观遗传修饰通过改变会影响风险差异靶基因表达。使用范围遍及表观基因组的方法，我们将利用独特的机会来探索从特征良好的治疗网络获得的DNA中的差异甲基化位置幼稚 MGU和MM的种群在利用最近的技术和分析进步的同时。这个项目利用现有的合作伙伴关系，资源和综合，高质量的临床数据和生物测量系统地收集在良好的治疗人群网络中，以改善我们的了解种族观察到的MGUS风险的不同趋势，并促进一组所需的生物标志物为了改善高危非裔美国人人口的MGUS临床课程的努力。