Genetic and Environmental risk of NAFLD-related HCC In All Latinos: the GENIAL Study

非酒精性脂肪性肝病(NAFLD)导致的肝细胞癌(HCC)负担增加 在过去的二十年里有很大的变化。尽管非酒精性脂肪肝和肝细胞癌对拉丁裔的影响不成比例 在评估肝癌风险的遗传和流行病学研究中，很少有拉丁裔人被包括在个人中。先验基因 研究包括拉丁裔在内的非酒精性脂肪肝风险的研究是有限的，因为他们使用候选基因方法。 无法检测到新的遗传关联。其他研究仅限于一个国家的个人， 因此无法考虑拉丁裔之间令人难以置信的多样性如何可能导致遗传风险或 非酒精性脂肪肝表型、肝硬变风险或肝细胞癌风险。在这项拟议的研究中，琼斯博士和弗洛雷斯博士将 作为多名首席调查员协同工作。与合作调查人员一起，他们将与其他 肝硬变网络(LCN)成员开发精确、个性化的非酒精性脂肪肝治疗方法 预测和肝癌风险分层专门针对拉美裔，这是一个易受伤害的群体 疾病负担。在目标1中，弗洛雷斯和琼斯博士将利用两项研究(UCLA ATLAS)的现有数据 社区健康倡议和NIH我们所有人研究计划)进行全基因组关联研究 (Gwas)，全表型关联研究，并在非酒精性脂肪肝患者中创建多基因风险评分。我们所有人 和ATLAS的目标是招募不同的参与者，以确保精准医学的包容性和普适性 研究。因此，拟议的研究代表了NAFLD中规模最大、种族最多样化的GWAs，有21,199人 已经确诊的非酒精性脂肪肝患者。我们将定义已知单曲和新奇单曲之间的关系 核苷酸多态(SNPs)与NAFLD、NASH、NAFLD-肝硬变和NAFLD-肝细胞癌的风险 种族、原产地和遗传血统。在与LCN调查人员的合作下，Flores博士和Jones博士将 将患有非酒精性脂肪肝的拉丁裔参与者纳入一项前瞻性病例对照研究，旨在表征基因- 已知和新的NAFLD相关SNP与环境风险的环境相互作用 包括艾滋病毒、糖尿病和代谢综合征在内的因素。他们将与新的和现有的LCN队列合作 参与者以及在迈阿密大学(UM)、迈阿密大学(UM)、 加州大学洛杉矶分校(UCLA)和波多黎各大学综合癌症中心(UPRCCC)。全 网站将识别和招募患有NAFLD和健康对照的新病例。我们将制定多基因风险评分 结合遗传、临床、社会文化、行为和环境特征来预测(1)风险 NAFLD患者的肝硬变，(2)NAFLD患者的肝功能失代偿，(3)肝细胞癌 伴有或不伴有肝硬变的NAFLD患者的风险。NAFLD是美国增长最快的肝硬变原因， 对拉丁美洲人的影响不成比例，他们也是肝癌负担最高的人。通过识别最强的风险 非酒精性脂肪肝表型、肝硬变失代偿和肝癌风险差异的驱动因素 通过拉丁裔样本，我们可以确定风险最高的人群，并对可改变的风险因素进行干预。

The burden of hepatocellular carcinoma (HCC) due to non-alcoholic fatty liver disease (NAFLD) has increased substantially over the past two decades. Although both NAFLD and HCC disproportionately affect Latino individuals, few Latinos were included in genetic and epidemiologic studies evaluating HCC risk. Prior genetic studies examining NAFLD risk that did include Latinos were limited in that they used candidate-gene approaches which cannot detect novel genetic associations. Other studies limited inclusion to individuals from one country, and thus could not consider how the incredible diversity among Latinos might drive genetic risk or differences in NAFLD phenotype, risk of cirrhosis, or HCC risk. In the proposed study, Drs. Jones and Flores will work collaboratively as multiple principal investigators. Along with co-investigators, they will collaborate with other members of the Liver Cirrhosis Network (LCN) to develop precise, personalized approaches to NAFLD prognostication and HCC risk stratification targeted specifically to Latinos, a vulnerable population with excess disease burden. In Aim 1, Drs. Flores and Jones will leverage existing data from two studies (UCLA ATLAS Community Health Initiative and NIH All of Us Research Program) to conduct a genome wide association study (GWAS), phenome-wide association study, and create polygenic risk scores in persons with NAFLD. All of Us and ATLAS aim to enroll diverse participants to ensure inclusivity and generalizability in Precision Medicine research. As such, the proposed study represents the largest, most racially diverse GWAS in NAFLD with 21,199 individuals with NAFLD already identified. We will define the relationship between known and novel single nucleotide polypmorphisms (SNPs) and risk of NAFLD, NASH, NAFLD-cirrhosis, and NAFLD-HCC, stratified by race, region of origin and genetic ancestry. In collaboration with LCN investigators, Drs. Flores and Jones will enroll Latino participants with NAFLD into a prospective case-control study that aims to characterize gene- environment interactions between known and novel genetic NAFLD-associated SNPs and environmental risk factors including HIV, diabetes, and metabolic syndrome. They will engage new and existing LCN Cohort participants as well as participants enrolled in existing cohorts at the University of Miami (UM), the University of Los Angeles California (UCLA) and the University of Puerto Rico Comprehensive Cancer Center (UPRCCC). All sites will identify and recruit new cases with NAFLD and healthy controls. We will develop polygenic risk scores that incorporate genetic, clinical, sociocultural, behavioral, and environmental characteristics to predict (1) risk of cirrhosis in persons with NAFLD, (2) hepatic decompensation in NAFLD patients with cirrhosis, and (3) HCC risk in NAFLD patients with or without cirrhosis. NAFLD is the fastest growing cause of cirrhosis in the US and disproportionately impacts Latinos who also have the highest HCC burden. By identifying the strongest risk factors that drive differences in NAFLD phenotype, cirrhosis decompensation, and HCC risk in a large, diverse Latino sample, we can identify those at greatest risk and intervene on modifiable risk factors.