Pirola CJ, Salatino A, Sookoian S. Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system. World J Gastroenterol 2021; 27(4): 305-320 [PMID: 33584064 DOI: 10.3748/wjg.v27.i4.305]
Corresponding Author of This Article
Silvia Sookoian, FAASLD, MD, PhD, Senior Scientist, Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Combatientes de Malvinas 3150, Ciudad Autónoma de Buenos Aires 1427, Argentina. ssookoian@intramed.net
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Jan 28, 2021; 27(4): 305-320 Published online Jan 28, 2021. doi: 10.3748/wjg.v27.i4.305
Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system
Carlos Jose Pirola, Adrian Salatino, Silvia Sookoian
Carlos Jose Pirola, Adrian Salatino, Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
Carlos Jose Pirola, Adrian Salatino, Silvia Sookoian, Institute of Medical Research A Lanari, University of Buenos Aires, School of Medicine, Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
Silvia Sookoian, Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
Author contributions: Pirola CJ contributed to study concept and design, data acquisition, data analysis and interpretation, statistical analysis, manuscript drafting, general study supervision and securing funding; Salatino A contributed to data acquisition and bioinformatic support; Sookoian S contributed to study concept and design, data acquisition, data analysis and interpretation, general study supervision, manuscript drafting, securing funding; Pirola CJ and Sookoian S should be considered joint senior authors.
Conflict-of-interest statement: No potential conflicts of interest. No financial support.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Silvia Sookoian, FAASLD, MD, PhD, Senior Scientist, Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Combatientes de Malvinas 3150, Ciudad Autónoma de Buenos Aires 1427, Argentina. ssookoian@intramed.net
Received: November 9, 2020 Peer-review started: November 9, 2020 First decision: December 8, 2020 Revised: December 19, 2020 Accepted: December 27, 2020 Article in press: December 27, 2020 Published online: January 28, 2021
Abstract
Genome-wide association studies of complex diseases, including nonalcoholic fatty liver disease (NAFLD), have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits — a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies. We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD. We used information retrieved from large public National Health and Nutrition Examination Surveys, Genome-wide association studies, and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits. Next, we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis, and genes that modulate hematological-related traits—specifically platelet count. We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets. Genes associated with platelet count are most highly expressed in the liver, followed by the pancreas, heart, and muscle. Conversely, genes associated with NAFLD presented high expression levels in the brain, lung, spleen, and colon. Functional mapping, gene prioritization, and functional analysis of the most significant loci (P < 1 × 10-8) revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways. In conclusion, variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits, particularly platelet count. Likewise, significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways. Hence, this approach yields novel mechanistic insights into NAFLD pathogenesis.
