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

描述（由申请方提供）：意义不明的单克隆丙种球蛋白病（MGUS）是一种常见的恶性前浆细胞疾病，分别见于3.2%和5.3%的50岁和70岁以上个体（凯尔RA，NEJM，2006）。MGUS的特征是单克隆血清免疫球蛋白、血栓形成风险增加、骨质疏松症和骨折风险增加以及发生恶性肿瘤的风险（主要是多发性骨髓瘤，每年1%）（REFS凯尔RA，NEJM，2002）。MGUS具有遗传风险的重要组成部分，并且在非裔美国人中的发病率高出2-3倍，并且在MGUS患者的家庭成员中的发病率高出2倍。既没有遗传基础，也没有环境因素导致MGUS/MM风险的定义。我们的长期目标是在详细了解MGUS/MM遗传学的基础上制定筛查和预防策略。几十年前描述的C57 BL/KaLwRij（KaLwRij）小鼠品系（Radl J，Clin Exp Immunol，1984）以高频率发展MGUS，具有人类疾病的许多相同特征，包括发展MM的风险增加。由于MGUS/MM中发生的最常见的体细胞突变是涉及免疫球蛋白重链转换区的染色体易位，我们的假设是生殖系对MGUS的易感性是异常免疫球蛋白同种型转换的结果。我们发现，通过ELISA的抗体同种型反应之间的高度显着差异KaLwRij和11个单独的小鼠品系。我们还发现，电离辐射和维生素D剥夺，与MM相关的两个环境因素，诱导小鼠抗体反应的显着和应变特异性的变化。为了加深我们对MGUS/MM风险的理解，我们提出：具体目标1：描述电离辐射、维生素D缺乏和菌株背景对小鼠免疫球蛋白同种型反应和单克隆丙种球蛋白病（MGUS）发展的影响;具体目标2：绘制MGUS/MM风险的数量性状基因座（QTL），并确定与疾病进展相关的体细胞突变。SA 1中的实验将为菌株和相关环境因素对MGUS发育的影响提供有价值的见解。SA 2中的实验将提供MGUS特异性QT数据集和匹配的DNA样品，这将允许我们鉴定小鼠中与MGUS风险相关的QTL。这些小鼠将被用作探索遗传性MGUS风险与环境因素之间关系的平台，我们生成的数据将为正在进行的人类全基因组关联（GWA）研究提供信息（华盛顿大学和马约诊所之间的合作）。该项目将是确定人类中驱动MGUS和MM的遗传因素的协调努力的一部分。 公共卫生相关性：意义不明的单克隆丙种球蛋白病（MGUS）发生在3.2%的50岁以上的人中，在5.3%的70岁或以上的人中。MGUS患者发生血栓形成、骨折和进展为多发性骨髓瘤（MM）（一种总是致命的癌症）的风险增加。环境因素如维生素D缺乏和电离辐射与MM风险增加有关。MM风险和易感性的基因检测的确定将促进该项目的长期目标，即制定MGUS/MM的筛查和预防策略。

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.