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      Intelligible Heterogeneous Networks: In-Depth Definition of Lipid Lowering Treatments in Humans

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            Abstract

            Access to large quantities of diverse data types creates the opportunity to elucidate complex diseases and the heterogeneity of treatments effects. Yet, this opportunity also challenges to render the information ‘big data’ harbours interpretable and directly applicable to patient care. Here, we report intelligible heterogeneous networks defining the complex interactions between molecular effects in liver, plasma, and bile induced by simvastatin and ezetimibe, two of the most prescribed lipid-lowering drugs. The heterogeneous networks incorporate transcriptomics, methylomics, plasma and biliary biochemical parameters from the Stockholm Study, recruiting patients eligible for cholecystectomy and randomized to three active treatments, plus placebo, for four weeks before surgery. Identification of unique heterogeneous modules increases interpretability and leads to the identification of unique putative effects of the different treatments. Proof-of-concept validation in a pre-clinical human model confirms TMBIM6 to be targeted by ezetimibe, alone or in combination, supporting the validity of our network medicine approach at defining biological interactions and discovering new drug targets.

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            Author and article information

            Conference
            REPO4EU
            5 October 2023
            Affiliations
            [1 ] IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italia ( https://ror.org/02mgzgr95)
            [2 ] Cardio Metabolic Unit, Department of Laboratory Medicine, and Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden ( https://ror.org/056d84691)
            [3 ] ;
            [4 ] Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy. ( https://ror.org/01111rn36)
            [5 ] Cardio Metabolic Unit, Department of Laboratory Medicine, and Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden. ( https://ror.org/056d84691)
            [6 ] Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA ( https://ror.org/04b6nzv94)
            [7 ] Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy ( https://ror.org/01111rn36)
            [8 ] Department of Brain and Behavioral Sciences, Università di Pavia, 27100 Pavia, Italy ( https://ror.org/00s6t1f81)
            [9 ] Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, Milan, Italy ( https://ror.org/033qpss18)
            [10 ] IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy ( https://ror.org/02mgzgr95)
            [11 ] Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy ( https://ror.org/020dggs04)
            [12 ] Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden ( https://ror.org/00m8d6786)
            Article
            10.58647/REXPO.23023
            5665f1ba-4441-4621-9783-4c5f623b9811
            Authors

            Published under Creative Commons Attribution 4.0 International ( CC BY 4.0). Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source.

            RExPO23
            2
            Stockholm, Sweden
            25-26 October 2023
            History
            Product

            REPO4EU

            Categories

            Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
            Pharmacology & Pharmaceutical medicine
            Lipid lowering,statin,ezetimibe,cholesterol,heterogeneous networks,human,liver

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