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

FLIP Investigators, FLPGP Investigators

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)26-40
Number of pages15
JournalAging
Volume9
Issue number1
DOIs
StatePublished - 2017

Fingerprint

Quantitative Trait Loci
Alleles
Haplotypes
Liver
Electrophoretic Mobility Shift Assay
Nuclear Proteins
Genes
Single Nucleotide Polymorphism
Electrophoresis
Non-alcoholic Fatty Liver Disease
Messenger RNA
Population

Keywords

  • EQTL
  • Fibrosis
  • Gene
  • Haplotype
  • NAFLD
  • PNPLA3

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans. / FLIP Investigators; FLPGP Investigators.

In: Aging, Vol. 9, No. 1, 2017, p. 26-40.

Research output: Contribution to journalArticle

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title = "Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans",
abstract = "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.",
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author = "{FLIP Investigators} and {FLPGP Investigators} and Wanqing Liu and Anstee, {Quentin M.} and Xiaoliang Wang and Samer Gawrieh and Gamazon, {Eric R.} and Shaminie Athinarayanan and Liu, {Yang Lin} and Rebecca Darlay and Cordell, {Heather J.} and Daly, {Ann K.} and Aithal, {Guruprasad P.} and Mike Allison and Karine Clement and Dufour, {Jean Francois} and Felix Stickel and Sven Francque and {Van Gaal}, Luc and Vlad Ratziu and Michael Olivier and G{\"o}ring, {Harald H H} and James Wallace and Mathew Goldblatt and Richard Komorowski and Day, {Chris P.} and Naga Chalasani",
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T1 - Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans

AU - FLIP Investigators

AU - FLPGP Investigators

AU - Liu, Wanqing

AU - Anstee, Quentin M.

AU - Wang, Xiaoliang

AU - Gawrieh, Samer

AU - Gamazon, Eric R.

AU - Athinarayanan, Shaminie

AU - Liu, Yang Lin

AU - Darlay, Rebecca

AU - Cordell, Heather J.

AU - Daly, Ann K.

AU - Aithal, Guruprasad P.

AU - Allison, Mike

AU - Clement, Karine

AU - Dufour, Jean Francois

AU - Stickel, Felix

AU - Francque, Sven

AU - Van Gaal, Luc

AU - Ratziu, Vlad

AU - Olivier, Michael

AU - Göring, Harald H H

AU - Wallace, James

AU - Goldblatt, Mathew

AU - Komorowski, Richard

AU - Day, Chris P.

AU - Chalasani, Naga

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N2 - 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.

AB - 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.

KW - EQTL

KW - Fibrosis

KW - Gene

KW - Haplotype

KW - NAFLD

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