title: Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans.
abstract: The increased expression ofPNPLA3148Mleads to hepatosteatosis in mice. This study aims to investigate the genetic control of hepaticPNPLA3transcription 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) influencingPNPLA3transcription, 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 modulatePNPLA3transcription 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 ofPNPLA3148Min NAFLD is independent of the gene transcription in humans, which may be attributed to the high endogenous transcription level ofPNPLA3gene in human livers.
authors.affiliation: Department of Medicinal Chemistry and Molecular Medicine, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Liu
authors.affiliation: Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Quentin M
authors.initials: QM
authors.lastname: Anstee
authors.affiliation: Department of Medicinal Chemistry and Molecular Medicine, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA.|Department of General Surgery, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, P. R. China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology and Hepatology, Indiana Fatty Liver Disease Research Group, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Samer
authors.initials: S
authors.lastname: Gawrieh
authors.affiliation: Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60627, USA.|Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.affiliation: Department of Medicinal Chemistry and Molecular Medicine, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Shaminie
authors.initials: S
authors.lastname: Athinarayanan
authors.affiliation: Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Yang-Lin
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Darlay
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.affiliation: Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Day
authors.affiliation: Division of Gastroenterology and Hepatology, Indiana Fatty Liver Disease Research Group, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Naga
authors.initials: N
authors.lastname: Chalasani
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014158:Transcription, Genetic; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: NAFLD; PNPLA3; eQTL; fibrosis; gene; haplotype