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Background  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.Results  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.    Conclusions  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.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13148-021-01142-1.

A targeted multi-omics approach reveals paraoxonase-1 as a determinant of obesity-associated fatty liver disease