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

Lookup NU author(s): Professor Quentin AnsteeORCiD, Dr Yang-Lin Liu, Dr Rebecca Darlay, Professor Heather Cordell, Professor Ann DalyORCiD, Professor Chris Day



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


The increased expression of PNPLA3148M 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 PNPLA3148M 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.

Publication metadata

Author(s): Liu W, Anstee QM, Wang X, Gawrieh S, Gamazon ER, Athinarayanan S, Liu Y-L, Darlay R, Cordell HJ, Daly AK, Day CP, Chalasani N

Publication type: Article

Publication status: Published

Journal: Aging

Year: 2017

Volume: 9

Issue: 1

Pages: 26-40

Print publication date: 01/01/2017

Online publication date: 13/10/2016

Acceptance date: 28/09/2016

Date deposited: 06/06/2017

ISSN (electronic): 1945-4589

Publisher: Impact Journals LLC


DOI: 10.18632/aging.101067


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Funder referenceFunder name
Health-F2- 2009-241762
K24 069290
R21 DK090437