Genetic risk factors in African American colorectal cancer patients

非裔美国结直肠癌患者的遗传危险因素

• 批准号: 8545719
• 负责人: Nathan A. Ellis
• 金额: $ 18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545719
• 关键词: 15q23; 8q24; Accounting; Affect; African American; American; Bioinformatics; Biological Assay; Cancer Patient; Cell model; Colorectal Cancer; Communities; DNA Resequencing; Data; Databases; Early Diagnosis; Etiology; European; Factor Analysis; Family; Frequencies; Future; Genes; Genetic; Genetic Risk; Genotype; Goals; Health; Incidence; Lead; Linkage Disequilibrium; Logistic Regressions; Luciferases; Measurement; Messenger RNA; Molecular; Morbidity - disease rate; Persons; Population; Predisposition; Principal Investigator; Proteins; Public Health; Recommendation; Recording of previous events; Regression Analysis; Relative (related person); Relative Risks; Reporter; Risk; Risk Factors; Screening for cancer; Series; Signal Transduction; Single Nucleotide Polymorphism; Stratification; Structure; Targeted Resequencing; Technology; Testing; Therapeutic Intervention; Variant; base; cancer risk; case control; design; gene function; genetic association; genetic risk factor; genetic variant; genome wide association study; in vitro Assay; mortality; next generation sequencing; novel; public health relevance; screening; validation studies

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) represents a serious public health problem that affects African Americans (AA) disproportionately. Both incidence rates and morbidity and mortality is higher in AAs than in other Americans. Family history, that is, genetic risk, remains one of the most important factors in recommendations for screening. Recent genome-wide association studies have identified 10 independent regions harboring genetic risk factors in CRC in populations of European ancestry. Using single-nucleotide polymorphisms (SNPs) from these studies, we have obtained evidence of association in four of these regions in AA CRC. Our goal is to identify the functional genetic risk factors, quantify their effects, and determine their functions. To pursue this goal, we propose four Aims. (1) We will validate previously identified candidate CRC-associated regions in AA CRC cases and controls. We will use Sequenom genotyping and tag SNPs from these regions to identify SNPs associated with CRC in AAs. We will use 100 ancestry informative markers to perform a structured logistic regression analysis that takes into account possible population stratification based on ancestry. Because AAs are more diverse than European Americans, these studies will very likely lead to better localization of the genetic risk factors. (2) We will use Next Generation Sequencing (NGS) technology to conduct a resequencing analysis of each candidate genetic region in 96 (48 CRC and 48 controls) persons with CRC. The region that we resequence will be guided by the genes and linkage disequilibrium observed in each CRC-associated region. (3) We will better quantify the effects of the genetic risk factors in each region. We will perform a bioinformatics analysis to identify putative functional variants. These functional candidates along with our novel genetic variants in CRC-associated regions will be genotyped in up to 2000 AA cases and 2000 AA control. We will perform structured logistic regression analysis to obtain the strongest genotype relative risks in each CRC-associated regions. (4) The foregoing analyses will provide a short-list of candidate genetic risk factors for each CRC-associated region. We will begin to characterize the molecular basis of CRC risk for each region by functional assays designed based on the putative mechanism caused by the genetic variants (regulatory or enzymatic). Molecular assays (for example, luciferase reporter assays) will be designed to determine the functional impact of candidate genetic risk factors. PUBLIC HEALTH RELEVANCE: Colorectal cancer affects African Americans disproportionately relative to other Americans. The discovery of genetic risk factors associated with colorectal cancer predisposition is tantamount to a fundamental understanding of the etiology of this significant health problem and to recommendations for cancer screening. We have found several candidate regions that contain genetic risk factors in African Americans. These and other regions have been implicated in colorectal cancer risk by validated genetic associations. We will determine the functional genetic variants that increase risk by genetic and functional studies. These studies will have important implications for early detection and possibly therapeutic intervention among African Americans.

描述（由申请人提供）：大肠癌（CRC）代表了严重的公共卫生问题，对非裔美国人（AA）不成比例地影响。 AAS的发病率，发病率和发病率都比其他美国人高。家族史，即遗传风险，仍然是筛查建议中最重要的因素之一。最近的全基因组关联研究已经确定了欧洲血统人群中CRC遗传危险因素的10个独立区域。使用这些研究中的单核苷酸多态性（SNP），我们在AA CRC中的四个区域中获得了关联的证据。我们的目标是确定功能性遗传风险因素，量化其影响并确定其功能。为了实现这一目标，我们提出了四个目标。 （1）我们将在AA CRC病例和对照组中验证先前确定的候选CRC相关区域。我们将使用这些区域的序列基因分型和标记SNP来识别与AAS中CRC相关的SNP。我们将使用100个祖先信息标记来执行结构化的逻辑回归分析，该分析考虑了基于祖先的种群分层。由于AAS比欧美人更多样化，因此这些研究很可能会导致更好地定位遗传危险因素。 （2）我们将使用下一代测序（NGS）技术对96名（48个CRC和48个对照组）中的每个候选遗传区域进行重新方程分析。我们重新定位的区域将由每个CRC相关区域中观察到的基因和连锁不平衡的指导。 （3）我们将更好地量化每个区域遗传危险因素的影响。我们将执行生物信息学分析以识别推定的功能变体。这些功能性候选者以及我们在2000年AA病例和2000年AA控制的CRC相关区域中的新型遗传变异将进行基因分型。我们将执行结构化的逻辑回归分析，以获得每个CRC相关区域中最强的基因型相对风险。 （4）上述分析将为每个CRC相关区域提供候选遗传风险因素的简短名单。我们将通过基于遗传变异（调节或酶促）引起的推定机制设计的功能测定法（调节性或酶促）来表征每个区域CRC风险的分子基础。分子测定（例如，荧光素酶报告基因测定法）将旨在确定候选遗传危险因素的功能影响。 公共卫生相关性：大肠癌与其他美国人相对于非裔美国人的影响不成比例。发现与大肠癌易感性相关的遗传危险因素的发现与对这一重大健康问题的病因的基本了解和癌症筛查的建议有关。我们发现了几个候选地区，其中包含非裔美国人的遗传危险因素。这些区域和其他区域与已验证的遗传关联有关结直肠癌的风险。我们将确定通过遗传和功能研究增加风险的功能遗传变异。这些研究将对非裔美国人的早期发现以及可能的治疗干预具有重要意义。