Impact of Genetic susceptibility along the continuum from MGUS to MM

摘要 未确定意义的单克隆性伽马病(MGUS)是一种良性浆细胞疾病，常见于 人群(3-5%≥50年)，以无症状克隆性浆细胞增殖为特征。 尽管MGUS先于多发性骨髓瘤(MM)，每年的进展率为1%，但大多数(&gt；75%)MGUS 永远不会进步。MGUS还与感染、骨折、骨质疏松症、肾脏疾病的风险增加有关 损伤和血栓形成，其结果是发病率和死亡率。很少有风险因素被确定为 MGUS或MGUS进展为MM，非裔美国人(AA)血统是 最强的。确定更有可能进步的个人是很重要的，因为个人 多发性骨髓瘤发生前严密监测的MGUS预后较好。前期工作 通过家系研究和最近的基因组研究确定了与多发性骨髓瘤相关的遗传变异 广泛联合研究(GWAS)。然而，目前还没有关于MGUS的有力的遗传流行病学研究 ，据我们所知，没有人调查过是否检测到 基因变异改善了高危MGU的识别，包括进展为MM的MGU。 因此，我们建议综合评估MGUS(目标1)和MGUS的遗传易感性 在欧洲裔美国人中使用已建立的流行病学和基因组研究进展到多发性骨髓瘤(AIM 2) (EA)。考虑到AA中MGUS和MM的种族易感性，我们首次建议评估 已知的MM易感变种和AAS AIMS 1-2中确定的新变种(AIMS 3)。两者都使用 我们将回答以下问题：(1)什么是 遗传变异和易患MGUS的基因(目标1)？(2)这些与遗传相比如何？ 从MGUS进展到MM的易感性(目标2)？(3)这些已识别的遗传因素 (以及由此产生的多基因风险评分，PR)区分有进展和无进展的MGUS患者 主动MM(目标2)？最后，(4)MGUS的风险和进展的这些遗传因素是否相似 EA和AA祖先的种群(目标3)？我们将利用已建立的MGUS的EA和AA研究，并 MGUS进展到MM(MM与MGUS)，大多数GWAS患者，以允许发现和验证。我们 还将利用基因组数据，包括全血(外周血单核细胞)的RNA测序 MGUS患者外周血中CD138+细胞和CD138+骨髓浆细胞(BMPC)提供基因信息 TWAs的表达。此外，我们将对新基因或变种进行功能表征 在EA和AA人群中均已验证。完成后，我们的研究将验证和鉴定生殖系 遗传因素与MGUS和进展为多发性骨髓瘤的风险相关。它会有很高的 影响，提供对MGUS和MM病因的洞察，并告知临床风险模型的遗传贡献 为数百万患有MGUS的人的进步而努力。

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.