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.

抽象的本研究的目的是确定 DNA 甲基化组对增加以下风险的影响：与非洲裔美国人相比，在非裔美国人中观察到意义不明的单克隆丙种球蛋白病 (MGUS) 欧洲裔美国人。促进对表观遗传修饰的更好理解。根据种族观察到的 MGUS 风险的不同趋势，我们将解决 MMDPQ1：哪些风险因素，单独或在其中合作，解释意义未明的单克隆伽马病（MGUS）发病率的变化在不同种族中，MGUS 先于多发性骨髓瘤 (MM)，这是最常见的血液癌症影响非裔美国人，其特点是细胞对细胞凋亡的抵抗导致延长生存期和克隆扩增、细胞遗传学异质、产生抗体的肿瘤细胞在骨中积累与非裔美国人相比，骨髓和髓外部位的 MGUS 风险高 2 至 3 倍。欧洲裔美国人及其他一些已确定的风险因素（种族、男性、肥胖、家族史）尽管有证据表明，对于观察到的 MGUS 风险差异，人们知之甚少。生殖系成分、DNA 序列的遗传改变本身并不能解释这种差异。表观基因组学为表征基因活性的遗传变化或种系可塑性提供了新的机会由于过去的环境暴露而产生的变化，这可以显着提高我们对 MGUS 的理解病因学、血统差异，并为改善高危人群的临床监测提供新的见解。我们将检验以下总体假设：不同的甲基化组特征与 MGUS 的过度风险相关在非裔美国人中观察到，异常的表观遗传修饰通过改变使用全表观基因组方法，我们将利用一个独特的机会来探索。从特征明确、未经治疗的网络中获得的 DNA 中的差异甲基化位置 MGUS 和 MM 群体，同时利用最新的技术和分析进步。利用现有的合作伙伴关系、资源以及全面、高质量的临床数据和生物样本系统地收集在一个特征明确的未接受治疗人群网络中，以改善我们的了解不同种族观察到的 MGUS 风险的不同趋势，并推进一套所需的生物标志物改进对高危非裔美国人人群 MGUS 临床病程的预测和管理。