P-6: Identifying high-risk genotypes for MM

P-6：识别 MM 高风险基因型

• 批准号: 7507320
• 负责人: Wendy Cozen
• 金额: $ 21.32万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7507320
• 关键词: Accounting; Affect; African American; B cell differentiation; Case-Control Studies; Cohort Studies; Computer software; Core Facility; DNA; DNA Repair Gene; Development; Family member; Follow-Up Studies; Gene Structure; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Growth Factor; Hawaii; Health Professional; Hispanics; Individual; Insulin-Like Growth Factor I; Interleukin-6; Link; Multiple Myeloma; Nurses' Health Study; Pathogenesis; Pathway interactions; Pilot Projects; Plasma Cells; Population; Population Study; Predisposition; Prevention strategy; Reproduction spores; Risk; Sample Size; Sampling; Variant; base; cell growth; ethnic minority population; genotyping technology; interest; programs

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.

尽管在理解多发性骨髓瘤的发病机理方面取得了进步，但它的原因仍然存在 难以捉摸。病例家庭成员的风险增加了1.5-3倍，表明遗传贡献。这是 在B细胞分化中重要的血浆细胞生长因子和蛋白质可能导致风险 通过增加可用于转化为骨髓瘤的浆细胞池。在先前的孢子中支持 试点研究，我们发现了控制两个重要的基因中多态性（即“ SNP”）的证据 血浆细胞生长因子，白介素（IL）-6和胰岛素样生长因子（IGF）-1，具有易感性 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前假设，但样本量很小，并且 因此，假阳性结果的可能性为a。忧虑。此外，由于多发性骨髓瘤 不成比例地影响非裔美国人和西班牙裔（在较小程度上），重要的是 在多种族环境中的研究，而试点研究的研究包括相对较少的少数民族。所以 我们建议在559例较大的多民族样本中确认这些初步发现和885例 来自现有DNA样本的5个单独研究的控件，包括卫生专业人员随访 研究，护士的健康研究和USC-Hawaii多种族队列研究以及两个基于人群的研究 病例对照研究。我们将在浆细胞生长和B细胞分化中包括几个基因 途径。在选择本研究中检查的SNP时，我们将考虑到 参与的研究人群以及与感兴趣基因结构有关的考虑因素。我们 已经开发了一个功能强大的软件程序，以根据这些考虑来选择多态性 hapmap，我们将使用精心验证，有效的基因分型技术在25个基因中的基因型1,536个SNP 通过DSC基因分型核心设施。我们将检查单个基因变异的关联 有骨髓瘤的风险，考虑了SNP之间的相关性。我们还将与其他孢子互动 询问我们观察到与风险相关的任何SNP的功能的项目。我们相信这一点 项目通过理解遗传来增强孢子的总体价值 对多发性骨髓瘤的敏感性，需要制定治疗和预防策略。