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

摘要 非酒精性脂肪性肝病（NAFLD）是儿科人群中最常见的慢性肝病 预计在未来10年内患病率将增加20%。儿童NAFLD的可能性大于 成年人的特点是肝细胞损伤的门静脉区域，反映了更严重的疾病类型。拉丁裔 是美国最大和增长最快的族裔群体之一，受NAFLD的影响不成比例， 包括肝硬化的患病率是全国平均水平的9倍。Omics数据集成，包括 基因组学、表观遗传学、转录组学、蛋白质组学、代谢组学和微生物组学，可以提供关于 生物途径的失调，并可能有助于确定风险因素和NAFLD的早期分子指标 风险和疾病进展及严重程度。在儿科NAFLD背景下研究这些特定的组学层 特别重要的是要确定可改变和不可改变的风险因素， 这种疾病。环境污染物暴露是可改变的暴露，可导致肝损伤， 导致NAFLD风险和疾病进展及严重程度。许多广泛的化学污染物 在动物模型中与脂肪肝疾病有关，包括持久性工业污染物，有毒金属， 杀虫剂和增塑剂。以前的人类研究强调了一些局限性，如样本量小，交叉， 部分研究设计，缺乏NAFLD表型的金标准成像方法，缺乏对NAFLD表型的关注。 拉丁美洲人，他们受到NAFLD的影响。因此，作为对RFA-HG-22-008的回应，我们建议 第一次也是最大的纵向调查，整合多组学特征，环境暴露， 以及社会和行为因素，以检测和评估表征病因的分子“概况”， NAFLD在拉丁美洲青年中的进展。我们的具体目标是：（1A）检查多个之间的关联 拉丁美洲青年的环境暴露与儿童NAFLD风险、疾病进展和严重程度;（1B） 评估这些关系是否受到社会因素、行为因素和遗传因素的影响。 （2A）鉴定将用作NAFLD风险和疾病的生物标志物的组学特征 （2B）评估这些特征是否被社会和行为因素改变; 以及（3）整合多组学数据、环境暴露、健康的社会决定因素和临床数据， 确定NAFLD风险的精确风险特征，以及疾病进展和严重程度。总的来说，这项研究将 增加我们对拉丁裔儿童NAFLD风险和疾病进展的了解，他们面临越来越多的 疾病的负担更高。研究结果可能具有广泛的临床和公共卫生意义，包括 高风险人群中儿科NAFLD的精确预防方法。

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.