Impact of Genetic susceptibility along the continuum from MGUS to MM (Supplement)

摘要 本申请是响应特别利益通知(NOSI)而提交的，而不是CA-22-057。 多发性骨髓瘤(MM)及其先兆、不明原因的单克隆性伽马病存在种族差异 重要性(MGUS)；与白色相比，MGUS和MM在黑人中的普遍程度至少是白人的两倍 人口，包括年龄较小的儿童。在一个人口中，MGUS也出现了类似的两倍增长- 基于加纳黑人男性样本与白人参考人群的比较，表明差异 在美国以外也是类似的。MGUS也是家族性的，在一级亲属中患病率增加2-3倍 多发性骨髓瘤或其他血液系统恶性肿瘤。虽然MGUS通常是良性的，但在50岁的人中很常见 和年龄较大的人，以每年1-1.5%的速度进展为MM或其他淋巴增殖性增生性疾病， 并与感染、骨折、骨质疏松症、肾损伤和血栓形成的风险增加有关， 以及由此导致的发病率和死亡率。因此，了解MGUS的发展和MGUS的进展 对多发性骨髓瘤很重要，特别是对那些风险最高的人，包括非洲血统的人(AA) 以及MM和血液病的一级亲属。我们的母基金(U01 CA271014)建议 应用ESTABLISE综合评估MGUS和MGUS进展为MM的遗传易感性 流行病学和基因组研究。由于种族易感性的重要性，我们第一次 建议评估已知的MM易感性变异并确定MGUS和MGUS的新变异 再生障碍性贫血人群中的进展(亲本U01，目标3)。在本补充申请中，我们建立了一个新的 与尼日利亚圣约人大学的Rotimi博士进行全球合作，进行补充研究 MGUS在西非加强对MGUS和MGUS进展的遗传学研究 AA.在目标1中，我们将使用一种新的质谱分析方法来评估MGUS的流行率，在两个 尼日利亚40岁及以上的风险群体[以社区为基础的样本(N=300)和一级亲属 多发性骨髓瘤和血液病患者(N=100)的发病率]，并与美国人口发病率进行比较。这一目标 利用前列腺癌跨大西洋联盟网络的经验和现有基础设施 招募了1000多名参与者和一级亲属，其中包括10个尼日利亚临床站点。在目标2中，我们 将对MM(N=25)进行基因分型，通过筛选目标1样本确定MGUS(N=66)， 以及未受影响的参与者样本(N=100)，以帮助验证遗传风险因素 在AA人群中，MGUS风险和MGUS进展为MM，如我们的父母U01所建议的。最后，我们 将建立MGUS、MM和相关疾病的家族研究，并在25日进行完整的外显子组测序 以确定罕见的变异。MGUS的患病率和MGUS的遗传决定因素 进展将对西非人口产生很大影响，因为预期寿命继续下降 稳步上升，更多的人将患上MGUS、MM和其他与衰老相关的疾病。

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI), NOT-CA-22-057. Racial disparities exist for multiple myeloma (MM) and its precursor, monoclonal gammopathy of undetermined significance (MGUS); both MGUS and MM are at least twice as common in Black compared with White populations, including at younger ages. A similar two-fold increase in MGUS has been seen in a population- based sample of Black men in Ghana compared to a White reference population, suggesting that the disparity is similar outside of the US. MGUS also is familial, with 2-3-fold increased prevalence in first-degree relatives of MM or other hematologic malignancies. Although MGUS is usually benign, it is common in those ages 50 and older, progresses to MM or other lymphoproliferative proliferative disorders at rates of 1-1.5% per year, and is associated with increased risk of infection, fracture, osteoporosis, renal impairment, and thrombosis, with resultant morbidity and mortality. Thus, understanding the development of MGUS and MGUS progression to MM is important, particularly among those with the highest risk, including people of African ancestry (AA) and first-degree relatives of MM and hematologic disorders. Our parent grant (U01 CA271014) proposes a comprehensive evaluation of genetic susceptibility to MGUS and MGUS progression to MM using established epidemiologic and genomic studies. Due to the importance of racial predisposition, for the first time, we propose to evaluate known MM susceptibility variants and identified novel variants for MGUS and MGUS progression in an AA population (Parent U01, Aim 3). In this supplement application, we establish a new global collaboration with Dr. Rotimi at Covenant University in Nigeria to conduct complementary studies of MGUS in West Africa to enhance the genetic investigations of MGUS and MGUS progression among people of AA. In Aim 1, we will estimate the prevalence of MGUS using a novel mass spectrometry assay, in two risk groups ages 40 and older in Nigeria [a community-based sample (N=300) and first-degree relatives of MM and hematologic cancer patients (N=100)] and compare to US population-based rates. This aim leverages the experience and existing infrastructure of the Prostate Cancer Transatlantic Consortium network that recruited over 1000 participants and first-degree relatives, including ten Nigerian clinical sites. In Aim 2, we will conduct genotyping (GWAS) of MM (N=25), MGUS identified through screening Aim 1 samples (N=66), and a sample of unaffected participants (N=100) to contribute to the validation of genetic risk factors for MGUS risk and MGUS progression to MM in AA populations, as proposed in our parent U01. Finally, we will establish a family study of MGUS, MM and related disorders and perform whole exome sequencing on 25 relatives to identify rare variants. Understanding the prevalence of MGUS and genetic determinants of MGUS and progression will have high impact for West African populations, as life expectancies continue to see a steady rise, and more individuals will develop MGUS, MM, and other diseases associated with aging.