Longitudinal integration of environmental exposures, omics, and childhood NAFLD (LEON) Study

ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the pediatric population with a projected 20% increase in prevalence over the next 10 years. NAFLD in children is more likely than in adults to be characterized by hepatocyte injury in portal regions, reflecting a more severe disease type. Latinos are one of the largest and fastest growing ethnic groups in the US and are disproportionately affected by NAFLD, including a prevalence of cirrhosis that is 9 times the national average. Omics data integration, including genomics, epigenetics, transcriptomics, proteomics, metabolomics, and the microbiome, can provide insight on dysregulation of biological pathways and may help identify risk factors and early molecular indicators of NAFLD risk and disease progression and severity. Studying these specific omics layers in the context of pediatric NAFLD is particularly important to identify both modifiable and non-modifiable risk factors which predispose children to this disease. Environmental pollutant exposures are modifiable exposures that can cause liver injury and contribute to NAFLD risk and disease progression and severity. Numerous widespread chemical pollutants have been associated with fatty liver disease in animal models including persistent industrial pollutants, toxic metals, pesticides, and plasticizers. Previous human studies underscore limitations such as small sample sizes, cross- sectional study design, lack of gold standard imaging methods for NAFLD phenotyping, and lack of focus on Latinos, who are disproportionally affected by NAFLD. Therefore, in response to RFA-HG-22-008, we propose the first and largest longitudinal investigation to integrate multi-omic signatures, environmental exposures, and social and behavioral factors to detect and assess molecular “profiles” characterizing the etiology and progression of NAFLD in Latino youth. Our specific aims are to: (1A) Examine associations between multiple environmental exposures and pediatric NAFLD risk and disease progression and severity in Latino youth; (1B) Evaluate whether these relationships are modified by social factors, behavioral factors, and genetic predisposition; (2A) Identify omics signatures that will serve as biomarkers of NAFLD risk and disease progression and severity; (2B) Evaluate whether these signatures are modified by social and behavioral factors; and (3) Integrate multi-omics data, environmental exposures, social determinants of health and clinical data to identify precise risk profiles of NAFLD risk, and disease progression and severity. Collectively, this study will increase our understanding of NAFLD risk and disease progression in Latino children, who face increasingly higher burdens of the disease. Findings may have broad-reaching clinical and public health implications including precision prevention approaches for pediatric NAFLD in high-risk populations.