[Frontiers in Bioscience 17, 206-220, January 1, 2012]

Genetic determinants of acquired cholestasis: A systems biology approach

Silvia Sookoian1, Carlos Jose Pirola2

1Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autonoma de Buenos Aires, Argentina, 2Department of Molecular Genetics and Biology of the Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autonoma de Buenos Aires, Argentina

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Systems approach and mechanistic and therapeutic insights
3.1 .Evidence of multifactorial genetic basis
3.2 .Systems Biology-based approaches and gene-regulatory networks in the etiology of PSC, PBC, and ICP
3.3 .Identifying potential candidate genes for disease susceptibility based on the strategy of gene prioritization
4. Perspective
5. Acknowledgments
6. References

1. ABSTRACT

Cholestatic liver diseases encompass a complex spectrum of intrahepatic and cholangiocellular cholestasis, whose etiologies include genetic and environmental components. This review focuses on the role of the genetic component of three adult cholestatic diseases, namely, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and intrahepatic cholestasis of pregnancy (ICP). In particular, we integrate genomic, molecular, and physiological data to understand the putative interplay between the underlying genetic mechanisms involved in the susceptibility of these diseases. This approach is based on the hypothesis that a more integrative knowledge of the genetic determinants of cholestatic diseases may have a strong impact on the development of improved therapies. We also propose the strategy of gene prioritization to identity potential candidate genes for disease susceptibility, and show some examples of "leading genes of human cholestatic pathways". Finally, based on the hypothesis that common physiologic processes and molecular networks may influence the risk of adult cholestatic diseases, we used a candidate gene prioritization application based on the use of a protein-protein interaction network as part of the 'interactome'.