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

描述（由申请人提供）：不确定意义单克隆γ病（MGUS）是一种常见的恶性前浆细胞疾病，分别在50岁和70岁以上的人群中发现3.2%和5.3% （Kyle RA， NEJM, 2006）。MGUS的特点是单克隆血清免疫球蛋白，血栓形成风险增加，骨质疏松和骨折风险增加，恶性肿瘤（主要是多发性骨髓瘤，每年1%）的风险增加（REFS Kyle RA， NEJM, 2002）。MGUS具有遗传风险的重要组成部分，非裔美国人的发病率高出2-3倍，MGUS患者的家庭成员的发病率高出2倍。导致MGUS/MM风险的遗传基础和环境因素均未明确。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（Radl J, clinin Exp Immunol, 1984）描述的C57BL/KaLwRij （KaLwRij）小鼠品系，发生MGUS的频率很高，具有许多与人类疾病相同的特征，包括发生MM的风险增加。由于MGUS/MM中最常见的体细胞突变是涉及免疫球蛋白重链开关区域的染色体易位，我们的假设是种系对MGUS的易感性是异常免疫球蛋白同型转换的结果。通过ELISA，我们发现KaLwRij和11个单独的小鼠品系在抗体同型反应上存在显著差异。我们还发现，电离辐射和维生素D剥夺这两个与MM相关的环境因素，在小鼠抗体反应中诱导了显著的和菌株特异性的变化。为了进一步了解MGUS/MM风险，我们提出：特异性目的1：表征电离辐射、维生素D剥夺和菌株背景对小鼠免疫球蛋白同型反应和单克隆γ病（MGUS）发展的影响；特异性目标2：绘制MGUS/MM风险的数量性状位点（QTL），并确定与疾病进展相关的体细胞突变。在SA1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。SA2的实验将提供MGUS特异性QT数据集和匹配的DNA样本，使我们能够识别与MGUS风险相关的小鼠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，我们产生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（华盛顿大学和梅奥诊所的合作努力）。该项目将成为确定驱动人类MGUS和MM的遗传因素的协调努力的一部分。

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.