Project Grant R01DK137764

GENOMIC IMPRINTING IN THE DEVELOPMENT OF NAFLD - ABSTRACT - GENOMIC IMPRINTING IN THE DEVELOPMENT OF NAFLD BY 2030, NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS PROJECTED TO AFFECT MORE THAN 100 MILLION AMERICANS, INCLUDING 10 MILLION CHILDREN. NAFLD RESULTS FROM OVERACCUMULATION OF FAT IN THE LIVER AND CAN PROGRESS TO NON-ALCOHOLIC STEATOHEPATITIS AND CIRRHOSIS, LEADING TO SIGNIFICANT MORBIDITY AND MORTALITY EVEN AMONG CHILDREN AND ADOLESCENTS. ACCUMULATING EVIDENCE INDICATES THAT EARLY LIFE EXPOSURES ALTER GENE EXPRESSION AND INFLUENCE THE RISK FOR NAFLD, BUT REGIONS OF THE GENOME TARGETED BY THESE EXPOSURES REMAIN UNCLEAR. WE HYPOTHESIZE THAT ABERRANT METHYLATION AT IMPRINT CONTROL REGIONS (ICRS), DISCRETE LOCI WHICH REGULATE EXPRESSION OF SPECIFIC GENES AND THE FUNCTION OF GENE NETWORKS, CONTRIBUTES SUBSTANTIALLY TO NAFLD. MEASURING THE IMPACT OF EPIGENETIC MODIFICATIONS THAT ALTER NAFLD RISK HAS BEEN CHALLENGING DUE TO THE LACK OF TOOLS FOR COMPREHENSIVE MEASUREMENT OF EPIGENETIC MODIFICATIONS, LONGITUDINAL DATA, COHORT DIVERSITY, ACCURATE NON-INVASIVE MARKERS OF LIVER FAT AND FIBROSIS, AS WELL AS THE TEMPORAL AMBIGUITY BETWEEN EXPOSURE AND OUTCOMES. TO OVERCOME THESE OBSTACLES, WE HAVE COMPREHENSIVELY IDENTIFIED DNA METHYLATION-CONTROLLED REGULATORY REGIONS FOR GENOMICALLY IMPRINTED GENES, MANY OF WHICH ARE IMPLICATED IN METABOLIC DISEASE, GROWTH AND DEVELOPMENT. ONCE ESTABLISHED IN THE GAMETES, THESE ICRS ARE STABLY TRANSMITTED DURING MITOTIC CELL DIVISION AND ARE THUS VERY SIMILAR ACROSS TISSUES. IMPORTANTLY, IMPRINTED GENES PLAY KEY ROLES IN GROWTH AND METABOLISM, UNDERSCORING PLAUSIBILITY IN THE ETIOLOGY OF NAFLD. THE OVERARCHING GOAL IS TO UTILIZE THESE NOVEL ICRS TO IDENTIFY METHYLATION CHANGES ASSOCIATED WITH NAFLD DEVELOPMENT. WE WILL LEVERAGE THE RESOURCES OF OUR MULTI- ETHNIC, PRE-BIRTH, LONGITUDINAL COHORT, THE NEWBORN EPIGENETICS STUDY (NEST) TO EVALUATE THE OLDEST 500 CHILDREN (17-21 YEARS). WE WILL IDENTIFY ICRS AT BIRTH ASSOCIATED WITH INCREASED LIVER FAT, NAFLD, AND LIVER FIBROSIS USING MAGNETIC RESONANCE IMAGING AS WELL AS INTERMEDIATE MARKERS OF NAFLD AND METABOLIC DYSFUNCTION. ICR METHYLATION WILL BE EXAMINED IN RELATION TO METABOLIC OUTCOMES, SEX, ETHNICITY AND EARLY LIFE EXPOSURES. A 1-YEAR FOLLOW-UP OF 200 ADOLESCENTS WILL DETERMINE STABILITY OF THE ASSOCIATIONS. FINALLY, WE WILL VALIDATE THE ICR STATUS OF NAFLD-ASSOCIATED GENES IN DIFFERENT TISSUE TYPES TO DETERMINE THEIR ABILITY TO SERVE AS EARLY MARKERS OF DISEASE RISK. THIS PROPOSAL WILL CONTRIBUTE SIGNIFICANTLY TO KNOWLEDGE ON THE RELATIONSHIP BETWEEN GENOMIC IMPRINTING AND NAFLD AND CLARIFY RISK- MEDIATING REGIONS AND EXPOSURES THAT CAN BE USED TO DEVELOP EARLY DETECTION AND THERAPEUTIC TOOLS TO COMBAT THE NAFLD EPIDEMIC.