P-6: Identifying high-risk genotypes for MM

尽管对多发性骨髓瘤发病机制的了解有所进展，但其原因仍然存在。 难以捉摸。在病例的家庭成员中，风险增加了1.5-3倍，这表明是遗传因素造成的。它是 B细胞分化过程中重要的浆细胞生长因子和蛋白质可能与风险有关 通过增加可用于转化为骨髓瘤的浆细胞池。在先前支持的孢子中 在初步研究中，我们发现了控制两个重要基因的基因多态(即S的单核苷酸多态)相关的证据 血浆细胞生长因子，白介素6和胰岛素样生长因子1，与易感性 多发性骨髓瘤。此外，我们发现某些DNA修复的多态之间存在正相关 基因与多发性骨髓瘤风险。这些研究之前的假设很强，但样本量很小，而且 因此，假阳性结果的可能性是一个令人担忧的问题。此外，由于多发性骨髓瘤 对非裔美国人和拉美裔美国人的影响不成比例(程度较小)，重要的是进行 多族裔背景下的研究，而试点研究包括相对较少的少数族裔。因此 我们建议在559例和885例多种族样本中证实这些初步发现。 来自现有DNA样本的5项独立研究的对照，包括卫生专业人员的随访 研究、护士健康研究和南加州大学-夏威夷多民族队列研究，以及两个基于人群的研究 病例对照研究。我们将包括几个与浆细胞生长和B细胞分化有关的基因 小路。在选择在这项研究中研究的SNPs时，我们会考虑到该地区的种族多样性。 参与研究的人群，以及与感兴趣基因结构有关的考虑。我们 我开发了一个功能强大的软件程序，基于这些考虑因素选择多态 HapMap，我们将使用经过充分验证的高效基因分型技术对25个基因中的1,536个SNPs进行基因分型 通过DSC基因分型核心设备。我们将研究个体基因变异之间的联系。 与骨髓瘤风险有关，说明了SNPs之间的相关性。我们也会与其他孢子互动 审问我们观察到的与风险相关的任何SNPs的功能的项目。我们相信这一点 该项目通过促进对遗传基因的理解来提高孢子的整体价值 多发性骨髓瘤的易感性是制定治疗和预防战略所必需的。

Although there are advances in understanding the pathogenesis of multiple myeloma, its causes remain elusive. Risk is increased by 1.5-3-fold in family members of cases, suggesting a genetic contribution. It is possible that plasma cell growth factors and proteins important in B cell differentiation may contribute to risk by increasing the pool of plasma cells available for transformation to myeloma. In prior SPORE supported pilot studies, we found evidence linking polymorphisms (i.e., "SNP"s) in genes that control two important plasma cell growth factors, interleukin (IL)-6 and insulin-like growth factor (IGF)-1, with susceptibility to multiple myeloma. In addition, we found positive associations between polymorphisms of certain DNA repair genes and multiple myeloma risk. These studies had strong prior hypotheses but small sample sizes, and thus the possibility of false positive results is a. concern. Furthermore, since multiple myeloma disproportionately affects African-Americans and Hispanics (to a lesser degree), it is important to conduct studies in a multi-ethnic setting, whereas the pilot studies included relatively few ethnic minorities. Therefore we propose to confirm these preliminary findings in a larger multi-ethnic sample of 559 cases and 885 controls from 5 separate studies with existing DNA samples, including the Health Professionals Follow-up Study, Nurse's Health Study, and the USC-Hawaii Multi-ethnic Cohort Study, and two population-based case-control studies. We will include several genes in plasma cell growth and B cell differentiation pathways. In choosing the SNPs to examine in this study, we will take into account the ethnic diversity of the participating study populations, as well as considerations related to the structure of the genes of interest. We have developed a powerful software program to choose polymorphisms based on those considerations from HapMap, and we will genotype 1,536 SNPs in 25 genes using well-validated, efficient genotyping technology through the DSC Genotyping Core Facility. We will examine the association of variation in individual genes with myeloma risk, accounting for correlations between SNPs. We will also interact with other SPORE projects to interrogate the function of any SNPs that we observe to be associated with risk. We believe this project enhances the overall value of the SPORE by contributing to the understanding of genetic susceptibility to multiple myeloma, needed for the development of both treatment and prevention strategies.