Impact of Genetic susceptibility along the continuum from MGUS to MM

从 MGUS 到 MM 连续体中遗传易感性的影响

• 批准号: 10436093
• 负责人: Elizabeth E Brown
• 金额: $ 69.49万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436093
• 关键词: ARID1A gene; African American; African American population; Age; American; Benign; Bone Marrow; CDKN2A gene; Case-Control Studies; Categories; Clinical; Clinical Research; Detection; Development; Disease; Early Intervention; Environmental Exposure; Epidemiology; Etiology; European; Evaluation; Family; Family Study; First Degree Relative; Fracture; Frequencies; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genomics; Genotype; Heritability; Heterogeneity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Impairment; Individual; KDM1A gene; Kidney; Light; Lymphoid Cell; Meta-Analysis; Modeling; Monitor; Monoclonal gammopathy of uncertain significance; Morbidity - disease rate; Multiple Myeloma; Nested Case-Control Study; Obesity; Osteoporosis; Outcome; Patients; Peripheral Blood Mononuclear Cell; Persons; Plasma Cells; Population; Predisposition; Prevention; Proteins; Race; Recording of previous events; Risk; Risk Factors; Subgroup; Susceptibility Gene; Thrombosis; Time; Tissues; Validation; Variant; Whole Blood; Work; base; biobank; clinical risk; cohort; cost effective; epidemiology study; exome sequencing; follow-up; genetic epidemiology; genetic risk factor; genetic variant; genome wide association study; genomic data; high risk; improved; infection risk; insight; mortality; multi-ethnic; novel; polygenic risk score; rare variant; screening; transcriptome; transcriptome sequencing

ABSTRACT Monoclonal gammopathy of undetermined significance (MGUS), is a benign plasma cell disorder, common in the population (3-5% ≥50 years) and characterized by an asymptomatic clonal plasma cell expansion. Although MGUS precedes multiple myeloma (MM) with progression rates of 1% per year, most (>75%) MGUS never progress. MGUS is also associated with increased risk of infection, fracture, osteoporosis, renal impairment, and thrombosis, with resultant morbidity and mortality. Few risk factors are identified for either the development of MGUS or MGUS progression to MM, with African American (AA) ancestry being one of the strongest. Identifying individuals who are more likely to progress is important given that individuals with MGUS who are closely monitored prior to development of MM have better outcomes. Prior work identified genetic variations associated with MM through family studies and, more recently, through genome wide association studies (GWAS). However, no well-powered genetic epidemiology studies of MGUS have been performed, particularly in AAs; and to our knowledge, none have investigated whether detection of genetic variation improves the identification of high-risk MGUS, including those that progress to MM. Therefore, we propose a comprehensive evaluation of genetic susceptibility to MGUS (Aim 1) and MGUS progression to MM (Aim 2) using established epidemiologic and genomic studies among European Americans (EA). Given the racial predisposition for MGUS and MM among AAs, for the first time, we propose to evaluate the known MM susceptibility variants and novel variants identified in Aims 1-2 in AAs (Aim 3). Using both GWAS and transcriptome-wide association studies (TWAS), we will answer the questions: (1) What are the genetic variations and genes predisposing to MGUS (Aim 1)? (2) How do these compare to genetic predisposition associated with progression from MGUS to MM (Aim 2)? (3) Do these identified genetic factors (and consequent polygenic risk scores, PRS) differentiate between MGUS patients that do and do not progress to active MM (Aim 2)? and finally, (4) Are these genetic factors for MGUS risk and progression similar across populations of EA and AA ancestries (Aim 3)? We will utilize established EA and AA studies of MGUS and MGUS progression to MM (MM vs. MGUS), the majority with GWAS, to allow for discovery and validation. We will also leverage genomic data, including RNA-sequencing of both whole blood (peripheral blood mononuclear cells, PBMCs) and sorted CD138+ bone marrow plasma cells (BMPCs) from MGUS patients to inform gene expression for the TWAS. Further, we will perform functional characterization of the new genes or variants validated in both EA and AA populations. Upon completion, our study will validate and characterize germline genetic factors associated with risk of MGUS and progression to MM in both EAs and AAs. It will have high impact, providing insight to MGUS and MM etiology and informing genetic contributions to clinical risk models for progression for the millions of people living with MGUS.

抽象的 不确定意义（MGU）的单克隆性伽马病是一种良性血浆细胞障碍，在 人口（3-5％≥50岁），其特征是不对称的克隆等离子体细胞扩张。 尽管MGU在多发性骨髓瘤（MM）之前，每年进展率为1％，但大多数（> 75％）MGU 永远不会进步。 MGU还与感染，骨折，骨质疏松症，肾脏的风险增加有关 损害和血栓形成，导致发病率和死亡率。很少有人确定任何风险因素 MGU或MGUS向MM的发展发展，非裔美国人（AA）血统是其中之一 坚强。鉴于个人，确定更有可能进步的个人很重要 在开发MM之前密切监测的MGU具有更好的结果。先前的工作 通过家庭研究确定了与MM相关的遗传变异，最近通过基因组鉴定 广泛的关联研究（GWAS）。但是，没有能力驱动的MGU遗传流行病学研究 进行了，特别是在AAS中；据我们所知，没有人调查是否检测 遗传变异改善了高危MGU的鉴定，包括发展为MM的MG。 因此，我们提出了对MGU（AIM 1）和MGU的遗传敏感性的全面评估 欧洲人使用已建立的流行病学和基因组研究的进展到MM（AIM 2） （ea）。鉴于AAS中MGU和MM的种族倾向，我们首次提议评估 在AAS中的AIMS 1-2中鉴定出的已知MM易感性变体和新型变体（AIM 3）。两者都使用 GWAS和全转录组协会研究（TWA），我们将回答以下问题：（1）什么是什么 遗传变异和基因易于mgus（目标1）？ （2）与遗传相比如何 与从MGU到MM的进展相关的倾向（AIM 2）？ （3）这些确定的遗传因素 （以及随之而来的多基因风险评分，PRS）区分毫无发展的MGU患者 到主动毫米（AIM 2）？最后，（4）是这些遗传因素是MGUS风险和进展的遗传因素 EA和AA祖先的种群（AIM 3）？我们将利用已建立的EA和AA研究， MGUS向MM（MM与MGUS）（大多数GWAS）的进展，以进行发现和验证。我们 还将利用基因组数据，包括对全血的RNA序列（外周血单核） 细胞，PBMCS）和分选的CD138+骨髓浆细胞（BMPC）来自MGUS患者，以告知基因 Twas的表达。此外，我们将执行新基因或变体的功能表征 在EA和AA种群中均得到验证。完成后，我们的研究将验证和表征种系 EAS和AAS中与MGU的风险以及向MM进展的风险相关的遗传因素。它会很高 影响，为MGU和MM病因提供见识，并为临床风险模型提供遗传贡献 用于数百万与MGU的人的进步。