Resequencing and Functional Studies to Identify Causal Gene Variants of Lymphoma

重新测序和功能研究以确定淋巴瘤的致病基因变异

基本信息

批准号：
8658805
负责人：
Jianqing Zhang
金额：
$ 53.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-22 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658805
关键词：
6p21.3 Accounting Address Affect African American Alleles Allelotyping Autoimmune Diseases Biological Case-Control Studies Cell Line Cessation of life Chemical Exposure Chromosome Band Chromosomes Chromosomes, Human, Pair 6 Computer Simulation DNA DNA Resequencing Disease Epidemiologic Studies Etiology European Exhibits Follicular Lymphoma Gene Frequency Genetic Genetic Variation Genomics Genotype Goals HLA-DQB1 HLA-DRB1 Hematologic Neoplasms Hematopoietic Neoplasms High-Throughput Nucleotide Sequencing In Vitro Individual Infectious Agent International Lead Link Linkage Disequilibrium Lymphocyte Lymphoma Lymphomagenesis Major Histocompatibility Complex Malignant Neoplasms Methods Minor Morbidity - disease rate Newly Diagnosed Non-Hodgkin&apos s Lymphoma Open Reading Frames Participant Pathway interactions Pattern Phenotype Population Population Attributable Risks Population Study Predisposition Process RNA Recording of previous events Research Research Personnel Risk Role Structural Genes Targeted Resequencing Testing Therapeutic Validation Variant Work base deep sequencing disorder risk genetic variant genome wide association study large cell Diffuse non-Hodgkin&apos s lymphoma lymphoblastoid cell line member mortality next generation next generation sequencing novel outcome forecast population based prevent rare variant risk variant screening validation studies

项目摘要

DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and the number one hematological malignancy worldwide. NHL has a major impact on morbidity and mortality; thus, studies that lead to the identification of causal gene variants will help to identify at-risk individuals through better screening; provide important clues to identify biological pathways/targets that may be amenable to therapeutic modulation; and provide new directions for studies that benefit lymphoma research. To accomplish this, resequencing targeted genomic regions known to be associated with NHL based on genome-wide association studies, followed by validation of potentially causal SNPs in large, well-phenotyped studies (such as in a consortium) is of utmost importance and will help to establish true causal genetic variants. Further characterization of causal gene variants is also crucial. Based on findings from two GWAS of NHL, SNPs and HLA alleles on chromosome band 6p21.32-33 in the major histocompatibility complex (MHC) region were associated with risk of follicular lymphoma (FL), one of the major subtypes of NHL. Our GWAS suggests an important genetic role exists for FL. MHC regions have been previously linked to some autoimmune disorders suggesting that they may share common risk alleles with FL. InterLymph member studies have identified additional susceptibility loci, some outside of the MHC, that have been validated within the consortium. Thus, there is a strong impetus to identify causal gene variants known to affect risk of FL and other NHL subtypes since no studies of this kind for lymphoma have been performed. To accomplish this, the following Aims will be undertaken: In Aim 1, targeted DNA capture and next generation sequencing will be implemented to identify all gene variants (rare and common SNPs and structural variants) in the MHC and in other regions associated with FL. The DNA has already been extracted from two large population-based case-control studies of NHL. Once novel and known SNPs are identified and tested for association with FL in the study populations, in silico functional analysis will be undertaken to predict causal SNPs. In Aim 2, putatively functional SNPs will be genotyped in independent case-control studies within the International Consortium of Investigators Working on NHL Epidemiologic Studies (InterLymph). In Aim 3, HLA allelotypes and SNPs will be assessed in African-American FL cases to help address the issue of high LD in European populations within the MHC. In Aim 4, validated SNPs will be functionally characterized. Accumulating evidence supports the role of genetic variation in the MHC with risk of many autoimmune diseases. Thus, the identification of causal gene variants in this region for lymphoma may also prove helpful in understanding other diseases sharing common susceptibility loci.

描述（由申请人提供）：非霍奇金淋巴瘤（NHL）是美国第五大常见的癌症，也是全球排名第一的血液系统恶性肿瘤。 NHL对发病率和死亡率有重大影响；因此，导致鉴定因果基因变异的研究将有助于通过更好的筛查来确定处于危险的人。提供重要的线索来识别可能适合治疗调节的生物途径/靶标；并为有益于淋巴瘤研究的研究提供新的方向。为此，基于基于全基因组关联研究的NHL的重新纠正已知与NHL相关的靶向基因组区域，然后在大型，良好的型研究中验证潜在的因果SNP（例如在财团中）非常重要，并且将有助于建立真正的因果遗传变异。因果基因变异的进一步表征也至关重要。基于来自NHL的两个GWA，SNP和HLA等位基因在主要组织相容性复合物（MHC）区域中染色体条带6P21.32-33的发现与NHL主要亚型的卵泡淋巴瘤（FL）的风险有关。我们的GWA提出了FL的重要遗传作用。 MHC地区以前与某些自身免疫性疾病有关，表明它们可能与FL共同具有共同的风险等位基因。 Interlymph成员研究已经确定了在财团内已验证的其他易感性基因座，一些MHC之外的一些位置。因此，由于尚未对淋巴瘤进行此类研究，因此有强大的动力来鉴定已知会影响FL和其他NHL亚型风险的因果基因变异。为此，将实现以下目标：在AIM 1中，将实现目标DNA捕获和下一代测序，以识别MHC中以及与FL相关的其他区域中的所有基因变体（稀有和常见的SNP和结构变体）。 DNA已经从NHL的两项基于人群的大型病例对照研究中提取。一旦确定了新颖和已知的SNP并测试了研究人群中与FL的关联，则将进行计算机功能分析以预测因果SNP。在AIM 2中，将在NHL流行病学研究（Interlymph）的国际研究人员联盟内的独立病例对照研究中进行基因分型。在AIM 3中，将在非洲裔美国佛罗里达州的案件中评估HLA的异型型和SNP，以帮助解决MHC内欧洲人口中的高LD问题。在AIM 4中，经过验证的SNP将在功能上表征。积累的证据支持遗传变异在MHC中的作用，并具有许多自身免疫性疾病的风险。因此，鉴定该区域中淋巴瘤的因果基因变异也可能有助于理解共享共同敏感位点的其他疾病。