Research Paper|Volume 9, Issue 1|pp 26—40

Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans

Wanqing Liu¹, Quentin M Anstee², Xiaoliang Wang^1,³, Samer Gawrieh⁴, Eric R. Gamazon^5,⁶, Shaminie Athinarayanan¹, Yang-Lin Liu², Rebecca Darlay⁷, Heather J Cordell⁷, Ann K Daly², Chris P Day², Naga Chalasani⁴

¹Department of Medicinal Chemistry and Molecular Medicine, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
²Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK
³Department of General Surgery, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, P. R. China
⁴Division of Gastroenterology and Hepatology, Indiana Fatty Liver Disease Research Group, Indiana University School of Medicine, Indianapolis, IN 46202, USA
⁵Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60627, USA
⁶Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37235, USA
⁷Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
⁸FLIP Investigator group members: Guruprasad P. Aithal (Nottingham, UK), Mike Allison (Cambridge, UK), Karine Clement (Paris, France), Jean-Francois Dufour, Felix Stickel (Bern, Switzerland), Sven Francque (Antwerp, Belgium), Luc Van Gaal (Antwerp, Belgium) and Vlad Ratziu (Paris, France).
⁹Fatty Liver Proteomic and Genomic Project (FLPGP) Investigators group members: Michael Olivier and Harald H. H. Göring (San Antonio, TX); James Wallace, Mathew Goldblatt, and Richard Komorowski (Milwaukee, WI).

* * Equal contribution

Received: June 15, 2016Accepted: September 28, 2016Published: October 13, 2016

https://doi.org/10.18632/aging.101067

Copyright: © 2016 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The increased expression of PNPLA3^148M leads to hepatosteatosis in mice. This study aims to investigate the genetic control of hepatic PNPLA3 transcription and to explore its impact on NAFLD risk in humans. Through a locus-wide expression quantitative trait loci (eQTL) mapping in two human liver sample sets, a PNPLA3 intronic SNP, rs139051 A>G was identified as a significant eQTL (p = 6.6×10^-8) influencing PNPLA3 transcription, with the A allele significantly associated with increased PNPLA3 mRNA. An electrophoresis mobility shift assay further demonstrated that the A allele has enhanced affinity to nuclear proteins than the G allele. The impact of this eQTL on NAFLD risk was further tested in three independent populations. We found that rs139051 did not independently affect the NAFLD risk, whilst rs738409 did not significantly modulate PNPLA3 transcription but was associated with NAFLD risk. The A-G haplotype associated with higher transcription of the disease-risk rs738409 G allele conferred similar risk for NAFLD compared to the G-G haplotype that possesses a lower transcription level. Our study suggests that the pathogenic role of PNPLA3^148M in NAFLD is independent of the gene transcription in humans, which may be attributed to the high endogenous transcription level of PNPLA3 gene in human livers.