Impact of Genetic susceptibility along the continuum from MGUS to MM

摘要 意义不明的单克隆丙种球蛋白病（MGUS）是一种良性浆细胞疾病，常见于 人群（3-5% ≥50岁），特征为无症状克隆性浆细胞扩增。 虽然MGUS先于多发性骨髓瘤（MM），每年的进展率为1%，但大多数（>75%）MGUS 从来没有进步。MGUS还与感染、骨折、骨质疏松症、肾功能衰竭、骨质疏松症和糖尿病的风险增加有关。 损伤和血栓形成，导致发病率和死亡率。很少有风险因素被确定为 发生MGUS或MGUS进展为MM，非裔美国人（AA）血统是其中一个 最强确定谁更有可能取得进展是很重要的，因为个人 在MM发展之前密切监测的MGUS患者具有更好的结果。先前工作 通过家族研究和最近的基因组研究， 广泛关联研究（GWAS）。然而，没有充分的遗传流行病学研究MGUS 特别是在AA中;据我们所知，没有人调查过是否检测到 遗传变异改善了高风险MGUS的识别，包括那些进展为MM的MGUS。 因此，我们建议对MGUS（Aim 1）和MGUS的遗传易感性进行综合评价， 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为MM（目标2） （EA）。鉴于AA中MGUS和MM的种族倾向，我们首次建议评估 已知的MM易感性变体和目标1-2中确定的AA中的新变体（目标3）。同时使用 GWAS和全转录组关联研究（TWAS），我们将回答以下问题：（1） 遗传变异和基因易感MGUS（目标1）？(2)这些与基因相比如何 与从MGUS进展为MM相关的易感性（目标2）？(3)这些已确定的遗传因素 (and随后的多基因风险评分，PRS）区分MGUS患者之间的进展和不进展 活动性MM（目标2）？最后，（4）这些MGUS风险和进展的遗传因素是否在不同的人群中相似？ EA和AA血统的人群（目标3）？我们将利用MGUS的既定EA和AA研究， MGUS进展为MM（MM vs. MGUS），大多数为GWAS，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） 细胞，PBMC）和来自MGUS患者的分选的CD 138+骨髓浆细胞（BMPC）以告知基因 TWAS的表达。此外，我们将对新基因或变异体进行功能表征 在EA和AA人群中得到验证。完成后，我们的研究将验证和表征生殖系 在EA和AA中，与MGUS风险和MM进展相关的遗传因素。它将有很高的 影响，提供对MGUS和MM病因学的见解，并为临床风险模型提供遗传贡献 为数百万患有MGUS的人提供治疗。

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.