Genetic risk factors in African American colorectal cancer patients

描述（由申请人提供）：结直肠癌（CRC）是一种严重的公共卫生问题，不成比例地影响非洲裔美国人（AA）。AAs的发病率、发病率和死亡率均高于其他美国人。家族史，即遗传风险，仍然是建议筛查的最重要因素之一。最近的全基因组关联研究已经确定了10个独立的区域，这些区域在欧洲血统的人群中具有CRC的遗传风险因素。使用单核苷酸多态性（SNPs）从这些研究中，我们已经获得了在AA CRC的这些区域中的四个关联的证据。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病例和对照中验证先前确定的候选CRC相关区域。我们将使用Sequenom基因分型和标记这些区域的SNP来鉴定与AA中CRC相关的SNP。我们将使用100个血统信息标记来进行结构化逻辑回归分析，其中考虑到基于血统的可能的人口分层。由于AA比欧洲裔美国人更多样化，这些研究很可能导致更好地定位遗传风险因素。(2)我们将使用下一代测序（NGS）技术对96例（48例CRC和48例对照）CRC患者的每个候选基因区域进行重新测序分析。我们重新测序的区域将由在每个CRC相关区域中观察到的基因和连锁不平衡指导。(3)我们将更好地量化每个地区遗传风险因素的影响。我们将进行生物信息学分析，以确定推定的功能变体。这些功能性候选物沿着我们在CRC相关区域中的新型遗传变异，将在多达2000例AA病例和2000例AA对照中进行基因分型。我们将进行结构化逻辑回归分析，以获得每个CRC相关区域中最强的基因型相对风险。(4)上述分析将提供每个CRC相关区域的候选遗传风险因素的入围名单。我们将开始通过基于遗传变异（调节或酶）引起的假定机制设计的功能测定来表征每个区域CRC风险的分子基础。将设计分子测定（例如，荧光素酶报告基因测定）以确定候选遗传风险因子的功能影响。 公共卫生相关性：结直肠癌对非洲裔美国人的影响相对于其他美国人不成比例。发现与结直肠癌易感性相关的遗传风险因素，等于对这一重大健康问题的病因学有了基本的了解，并提出了癌症筛查的建议。我们已经发现了几个候选区域，包含非裔美国人的遗传风险因素。这些区域和其他区域通过经验证的遗传关联与结直肠癌风险有关。我们将通过遗传和功能研究确定增加风险的功能性遗传变异。这些研究将对非裔美国人的早期发现和可能的治疗干预具有重要意义。

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.