Genome Wide Admixture Scan for Multiple Myeloma in African Americans

描述（由申请人提供）：多发性骨髓瘤（MM）是一种恶性肿瘤，由浆细胞的肿瘤克隆组成，终末分化的B淋巴细胞负责产生抗体。它是血液恶性肿瘤中第二常见的死亡原因。尽管最近治疗取得了进展，但5年生存率仍低于40%。非裔美国人的发病率比白人高2倍以上；疾病发病率的种族差异的原因尚不清楚。在有多发性骨髓瘤和/或其前体、未确定意义单克隆γ病（MGUS）家族史的人群中，风险也增加2- 3倍。我们假设多发性骨髓瘤风险存在遗传因素，非裔美国人的部分过度风险是通过遗传变异介导的。在这项应用中，我们建议进行全基因组关联研究，以确定非裔美国人人群中导致多发性骨髓瘤风险的常见遗传变异。更具体地说，我们将检查2072例非裔美国人多发性骨髓瘤病例和4645例非裔美国人对照中的1,000,000个遗传标记。本研究的病例将通过NCI/SEER基于人群的癌症登记处（加利福尼亚州，底特律，路易斯安那州和新泽西州）和6个非裔美国人人口众多地区的临床中心(阿拉巴马大学伯明翰分校，约翰霍普金斯大学，埃默里大学，Karmanos癌症研究所/韦恩州立大学，西北大学，芝加哥大学，和md安德森癌症中心/德克萨斯大学)。对照将包括来自美国各地的4,645名健康的未受影响的非裔美国人受试者。我们将通过对来自美国和澳大利亚的多项现有研究中1,500例MM病例和3,710例欧洲血统对照的前100个snp的关联测试来评估我们研究结果的普遍性。此外，与NCI顾问Landgren博士一起，我们将在700名患有MGUS的非裔美国人受试者和从NHANES招募的1400名对照组中检查风险变异与前体MGUS的关系。在本提案中，我们将利用协作的优势，大规模的基因研究，以确定共同的风险等位基因的人群（非裔美国人），经历了健康方面的差异，就这种癌症。除了阐明非裔美国人多发性骨髓瘤的病因学外，我们希望发现可以用于药物开发的新途径。我们的最终目标是减少非裔美国人因这种致命癌症而经历的健康差距。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a malignancy consisting of a neoplastic clone of plasma cells, the terminally-differentiated B lymphocytes responsible for antibody production. It is the second most common cause of death among the hematological malignancies. Despite recent advances in treatment, the 5-year survival rate remains under 40%. African Americans experience incidence rates over 2-fold higher than those of Whites; the reasons for the racial differences in disease rates are unknown. Risk is also 2- to 3-fold elevated among persons with a family history of multiple myeloma and/or its precursor, monoclonal gammopathy of undetermined significance (MGUS). We hypothesize that there is a genetic component to multiple myeloma risk and that part of the excess risk in African Americans is mediated through inherited variation. In this application, we propose to perform a genome-wide association study to identify common genetic variants that contribute to multiple myeloma risk in the African American population. More specifically, we will examine 1,000,000 genetic markers in 2,072 African American multiple myeloma cases and 4,645 African American controls. Cases for this study will be recruited and specimens collected by means of a network of collaborations with NCI/SEER population-based cancer registries (California, Detroit, Louisiana and New Jersey) and clinical centers in 6 regions with large African-American populations (University of Alabama at Birmingham, Johns Hopkins University, Emory University, Karmanos Cancer Institute/Wayne State University, Northwestern University, University of Chicago, and M.D. Anderson Cancer Center/University of Texas). Controls will consist of 4,645 healthy unaffected African-American subjects from across the U.S. We will assess the generalizabilty of our findings by association testing of the top 100 SNPs in 1,500 MM cases and 3,710 controls of European origin in multiple existing studies from the U.S. and Australia. In addition, with NCI consultant Dr. Landgren, we will examine the associations of the risk variants with the precursor, MGUS among 700 African-American subjects with MGUS and 1,400 controls recruited from NHANES. In this proposal we will utilize the strengths of collaborative, large-scale genetic research to identify common risk alleles for MM in a population (African American) that experiences a health disparity with respect to this cancer. In addition to illuminating etiology of multiple myeloma in African Americans, we hope to discover new pathways that can be exploited for drug development. Our ultimate goal is to reduce the health disparity experienced by African Americans due to this fatal cancer.