P-6: Identifying high-risk genotypes for MM

虽然对多发性骨髓瘤的发病机制有了进一步的了解，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，这表明遗传因素。是 浆细胞生长因子和在B细胞分化中起重要作用的蛋白质可能导致风险 通过增加可转化为骨髓瘤的浆细胞库。在之前的SPORE支持中， 初步研究中，我们发现了将多态性（即，控制两个重要基因的基因中的“SNP“） 血浆细胞生长因子，白细胞介素（IL）-6和胰岛素样生长因子（IGF）-1， 多发性骨髓瘤此外，我们发现某些DNA修复的多态性之间存在正相关， 基因和多发性骨髓瘤风险。这些研究有很强的先验假设，但样本量较小， 因此假阳性结果的可能性为a。关心此外，由于多发性骨髓瘤 不成比例地影响非洲裔美国人和西班牙裔美国人（在较小程度上），重要的是要进行 在多族裔背景下进行的研究，而试点研究包括的少数族裔相对较少。因此 我们建议在559例和885例更大的多种族样本中证实这些初步发现， 来自5项独立研究的对照，包括卫生专业人员随访 研究，护士的健康研究，和南加州大学夏威夷多种族队列研究，和两个基于人口的 病例对照研究。我们将包括几个基因在浆细胞生长和B细胞分化 途径。在选择SNPs进行研究时，我们将考虑到种族多样性。 参与研究的人群，以及与感兴趣的基因的结构有关的考虑。我们 已经开发了一个强大的软件程序，根据这些考虑因素选择多态性， 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SNP进行分型 基因分型核心设施我们将研究个体基因变异的关联 与骨髓瘤风险相关，解释SNP之间的相关性。我们还将与其他SPORE 项目询问我们观察到的与风险相关的任何SNP的功能。我们相信这 该项目通过促进对遗传学的理解，提高了孢子的整体价值。 多发性骨髓瘤的易感性，需要开发治疗和预防策略。

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.