Genetic risk factors in African American colorectal cancer patients

描述（由申请人提供）：结直肠癌（CRC）是严重的公共卫生问题，严重影响非裔美国人（AA）。AAs的发病率、发病率和死亡率都高于其他美国人。家族史，即遗传风险，仍然是推荐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个独立区域，在欧洲血统人群中存在CRC遗传风险因素。利用这些研究的单核苷酸多态性（snp），我们已经获得了AA CRC中四个这些区域的关联证据。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。为实现这一目标，我们提出四个目标。(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。我们将使用序列基因分型和标记来自这些区域的snp来鉴定与AAs中结直肠癌相关的snp。我们将使用100个祖先信息标记进行结构化逻辑回归分析，考虑到基于祖先的可能的人口分层。由于美国裔美国人比欧洲裔美国人更多样化，这些研究很可能会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例结直肠癌患者（48例结直肠癌患者和48例对照患者）的每个候选遗传区域进行重测序分析。我们重新排序的区域将由每个crc相关区域中观察到的基因和连锁不平衡引导。(3)更好地量化各区域遗传风险因素的影响。我们将进行生物信息学分析，以确定假定的功能变异。这些功能性候选者以及我们在crc相关区域的新基因变异将在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)上述分析将为每个crc相关区域提供候选遗传风险因素的简短列表。我们将开始描述每个区域CRC风险的分子基础，通过基于由遗传变异（调节或酶）引起的假定机制设计的功能分析。分子测定（例如，荧光素酶报告基因测定）将被设计用于确定候选遗传风险因素的功能影响。

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.