The multifactorial nature of non-alcoholic fatty liver disease cannot be explained solely by genetic factors. Recent evidence revealed that DNA methylation changes take place at proximal promoters within susceptibility genes. This emphasizes the need for integrating multiple data types to provide a better understanding of the disease’s pathogenesis. One such candidate gene is paraoxonase-1 (PON1). Substantial interindividual differences in PON1 are apparent and could influence disease risk later in life. The aim of this study was therefore to determine the different regulatory aspects of PON1 variability and to examine them in relation to the predisposition to obesity-associated fatty liver disease. A targeted multi-omics approach was applied to investigate the interplay between PON1 genetic variants, promoter methylation, expression profile and enzymatic activity in an adult patient cohort with extensive metabolic and hepatic characterisation including liver biopsy. Alterations in PON1 status were shown to correlate with waist-to-hip ratio and relevant features of liver pathology. Particularly, the regulatory polymorphism rs705379:C > T was strongly associated with more severe liver disease. Multivariable data analysis furthermore indicated a significant association of combined genetic and epigenetic PON1 regulation. This identified relationship postulates a role for DNA methylation as a mediator between PON1 genetics and expression, which is believed to further influence liver disease progression via modifications in PON1 catalytic efficiency. Our findings demonstrate that vertical data-integration of genetic and epigenetic regulatory mechanisms generated a more in-depth understanding of the molecular basis underlying the development of obesity-associated fatty liver disease. We gained novel insights into how NAFLD classification and outcome are orchestrated, which could not have been obtained by exclusively considering genetic variation.

中文翻译：

---

靶向多组学方法揭示对氧磷酶-1是肥胖相关脂肪肝的决定因素

非酒精性脂肪肝的多因素性质不能仅用遗传因素来解释。最近的证据表明，DNA 甲基化变化发生在易感基因内的近端启动子处。这强调了整合多种数据类型以更好地了解疾病发病机制的必要性。一种这样的候选基因是对氧磷酶-1 (PON1)。PON1 的显着个体间差异是显而易见的，并且可能会影响以后生活中的疾病风险。因此，本研究的目的是确定 PON1 变异性的不同调节方面，并检查它们与肥胖相关脂肪肝疾病易感性的关系。应用靶向多组学方法研究 PON1 遗传变异、启动子甲基化、在具有广泛代谢和肝脏特征（包括肝活检）的成年患者队列中的表达谱和酶活性。显示 PON1 状态的改变与腰臀比和肝脏病理学的相关特征相关。特别是，调控多态性 rs705379:C > T 与更严重的肝病密切相关。多变量数据分析进一步表明组合的遗传和表观遗传 PON1 调控的显着关联。这种确定的关系假定 DNA 甲基化作为 PON1 遗传学和表达之间的介质的作用，这被认为通过 PON1 催化效率的改变进一步影响肝脏疾病的进展。我们的研究结果表明，遗传和表观遗传调控机制的垂直数据整合产生了对肥胖相关脂肪肝发展的分子基础的更深入了解。我们对如何协调 NAFLD 分类和结果获得了新的见解，这无法通过仅考虑遗传变异来获得。