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

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.