ENVIRONMENT & GENETICS OF MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE (MGUS)

环境

• 批准号: 8177842
• 负责人: MICHAEL H TOMASSON
• 金额: $ 16.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8177842
• 关键词: African American; Age; Antibodies; Antibody Formation; Ascaridil; Bone Density; Chromosomal translocation; Clinic; Computer software; DNA; Data; Data Set; Development; Diet; Dimensions; Disease; Disease Progression; Dose; Electrophoresis; Environment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Family member; First Degree Relative; Fracture; Frequencies; Genes; Genetic; Genome Scan; Genotype; Goals; Heavy-Chain Immunoglobulins; Human; IgG1; IgG3; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin Isotypes; Immunoglobulin M; Immunoglobulins; Individual; Inherited; Ionizing radiation; Light-Chain Immunoglobulins; Malignant Neoplasms; Maps; Modeling; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Mouse Strains; Multiple Myeloma; Mus; Osteoporosis; Patients; Persons; Phenotype; Plasma Cells; Predisposition; Premalignant; Prevention strategy; Production; Protocols documentation; Quantitative Trait Loci; Resistance; Risk; Sampling; Screening procedure; Serum; Serum Proteins; Somatic Mutation; Testing; Thrombosis; Time; Two-Dimensional Gel Electrophoresis; Universities; Vitamin D; Vitamin D Deficiency; Washington; base; deprivation; genetic variant; genome wide association study; human disease; insight; research study; response

DESCRIPTION (provided by applicant): Monoclonal gammopathy of uncertain significance (MGUS) is a common, pre-malignant plasma cell disorder found in 3.2 and 5.3 percent of individuals over the ages of 50 and 70 years respectively (Kyle RA, NEJM, 2006). MGUS is characterized by monoclonal serum immunoglobulin, an increased risk of thrombosis, an increased risk of osteoporosis and bone fractures and a risk of developing malignancy (predominantly multiple myeloma at 1% per year (REFS Kyle RA, NEJM, 2002). MGUS has a significant component of inherited risk, and is found at 2-3 fold higher rates in African Americans, and 2-fold higher rates in family members of MGUS patients. Neither the genetic basis nor the environmental factors contributing to MGUS/MM risk have been defined. Our long-term goal is to develop screening and prevention strategies based on a detailed understanding of MGUS/MM genetics. The C57BL/KaLwRij (KaLwRij) mouse strain, described decades ago (Radl J, Clin Exp Immunol, 1984), develops MGUS at high frequency with many of the same features of the human disease including an increased risk of developing MM. Since the most common somatic mutations to occur in MGUS/MM are chromosomal translocations involving immunoglobulin heavy chain switch regions, our hypothesis is that germline susceptibility to MGUS is the consequence of abnormal immunoglobulin isotype switching. We found highly significant differences in antibody isotype responses by ELISA between KaLwRij and 11 separate mouse strains. We also found that ionizing radiation and vitamin D deprivation, two environmental factors associated with MM, induced significant and strain-specific changes in antibody responses in mice. To advance our understanding of MGUS/MM risks, we propose: Specific Aim 1: Characterize effects of ionizing radiation, vitamin D deprivation and strain background on immunoglobulin isotype responses and monoclonal gammopathy (MGUS) development in mice; Specific Aim 2: Map quantitative trait loci (QTL) for MGUS/MM risk and identify somatic mutations associated with disease progression. The experiments in SA1 will provide valuable insights into the effects of strain and relevant environmental factors to MGUS development. The experiments in SA2 will provide an MGUS-specific QT data set and matched DNA samples that will allow us to identify QTL's in mice associated with MGUS risk. These mice will be used as a platform to explore the relationship between inherited MGUS risk and environmental factors and the data we generate will inform ongoing genome-wide association (GWA) studies in humans (a collaborative effort between Washington University and the Mayo Clinic). This project will be part of a coordinated effort to identify the genetic factors that drive MGUS and MM in humans. PUBLIC HEALTH RELEVANCE: Monoclonal gammopathy of uncertain significance (MGUS) occurs in 3.2% of persons over the age of 50, and in 5.3% of individuals 70 years or older. MGUS patients are at increased risk for thrombosis, bone fractures and progression to multiple myeloma (MM), an invariably fatal cancer. Environmental factors such as vitamin D deficiency and ionizing radiation are associated with increased risk of MM. Identification of gene tests for MM risk and predisposition will facilitate the long-term goal of this project which is to develop screening and prevention strategies for MGUS/MM.

描述（由申请人提供）：不确定意义的单克隆性γ（MGUS）是一种常见的，预防性的血浆细胞疾病，分别在50岁和70岁的人群中分别为3.2％和5.3％（Kyle RA，NEJM，NEJM，2006）。 MGU的特征是单克隆血清免疫球蛋白，血栓形成的风险增加，骨质疏松症和骨骼骨折的风险增加以及发生恶性肿瘤的风险（主要是每年1％的多发性骨髓瘤，参考文献Kyle RA，NEJM，NEJM，2002年，MGUS的速度高2-3折叠。在MGUS患者的家庭中，遗传基础或有助于MGUS/MM风险的环境因素是我们的长期目标。在包括MG/mm中最常见的体细胞突变的人类疾病中，涉及免疫球蛋白重链开关区域的染色体易位是，我们的假设是MGUS对MGUS的易感性是异常的免疫球蛋白同种型开关。我们发现Kalwrij和11个单独的小鼠菌株之间ELISA的抗体同种型反应有很大的显着差异。我们还发现，与MM相关的两个环境因素的电离辐射和维生素D剥夺引起了小鼠抗体反应的显着和菌株特异性变化。为了促进我们对MGU/MM风险的理解，我们提出：特定目的1：表征电离辐射，维生素D剥夺的影响和对免疫球蛋白同种型反应的影响以及小鼠中的单克隆性γ-γ（MGUS）发育的影响；特定目的2：MAP定量性状基因座（QTL）用于MGUS/MM风险，并确定与疾病进展相关的体细胞突变。 SA1中的实验将为菌株和相关环境因素对MGUS发育的影响提供宝贵的见解。 SA2中的实验将提供MGUS特异性的QT数据集并匹配的DNA样品，这将使我们能够识别与MGUS风险相关的小鼠中的QTL。这些小鼠将被用作探索继承的MGU风险与环境因素之间的关系，而我们生成的数据将为整个基因组的研究（GWA）研究（华盛顿大学与梅奥诊所之间的合作努力）提供信息。该项目将是协调努力的一部分，以确定驱动人类MM和MM的遗传因素。 公共卫生相关性：具有不确定意义的单克隆性伽马病（MGU）发生在50岁以上的3.2％的人中，在70岁以上的个人中，有5.3％的人发生。 MGUS患者的血栓形成，骨折和多发性骨髓瘤（MM）的风险增加，这总是致命的癌症。维生素D缺乏和电离辐射等环境因素与MM风险增加有关。鉴定MM风险和倾向的基因测试将促进该项目的长期目标，即MGUS/MM制定筛查和预防策略。