The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients.
HCC
NAFLD
PSRC1
genetic variants
lipid metabolism
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
08 Apr 2021
08 Apr 2021
Historique:
received:
11
03
2021
revised:
31
03
2021
accepted:
01
04
2021
entrez:
30
4
2021
pubmed:
1
5
2021
medline:
1
5
2021
Statut:
epublish
Résumé
Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet. We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq ( The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension ( In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet.
METHODS
METHODS
We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (
RESULTS
RESULTS
The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (
CONCLUSIONS
CONCLUSIONS
In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively.
Identifiants
pubmed: 33917919
pii: cancers13081783
doi: 10.3390/cancers13081783
pmc: PMC8068289
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Ministero della salute
ID : GR-2019-12370172
Références
Int J Mol Sci. 2020 Apr 23;21(8):
pubmed: 32340286
Nutrients. 2019 Oct 29;11(11):
pubmed: 31671785
Clin Chim Acta. 2016 Sep 1;460:11-7
pubmed: 27312323
EBioMedicine. 2020 Feb;52:102658
pubmed: 32058943
Gastroenterology. 2020 May;158(7):1999-2014.e1
pubmed: 32044314
J Lipid Res. 2011 Nov;52(11):1885-926
pubmed: 21862702
Behav Brain Res. 2001 Nov 1;125(1-2):279-84
pubmed: 11682119
J Cardiol. 2014 Nov;64(5):339-46
pubmed: 24674750
Nature. 2010 Aug 5;466(7307):714-9
pubmed: 20686566
Oncogene. 1999 Dec 16;18(54):7765-74
pubmed: 10618717
J Clin Med. 2019 Dec 19;9(1):
pubmed: 31861591
Biochem Biophys Res Commun. 2008 May 2;369(2):567-72
pubmed: 18291097
PLoS One. 2011;6(11):e27481
pubmed: 22110658
Nat Genet. 2009 Mar;41(3):334-41
pubmed: 19198609
J Lipid Res. 2019 Jun;60(6):1144-1153
pubmed: 30918065
Gut. 2020 Oct;69(10):1855-1866
pubmed: 32001554
Nature. 2012 Nov 1;491(7422):56-65
pubmed: 23128226
Int J Mol Med. 2015 May;35(5):1451-9
pubmed: 25738804
Gastroenterology. 2016 May;150(5):1219-1230.e6
pubmed: 26850495
Atherosclerosis. 2010 Jan;208(1):183-9
pubmed: 19660754
Hepatology. 2016 Jul;64(1):73-84
pubmed: 26707365
Hepatology. 2005 Jun;41(6):1313-21
pubmed: 15915461
Sci Rep. 2017 Jul 3;7(1):4492
pubmed: 28674415
DNA Res. 2000 Jun 30;7(3):233-5
pubmed: 10907856
Curr Opin Lipidol. 2019 Jun;30(3):198-204
pubmed: 30946050
Biomed Rep. 2015 Jan;3(1):118-122
pubmed: 25469260
FEBS Lett. 1998 Jun 5;429(1):27-30
pubmed: 9657377
Hepatology. 2015 Feb;61(2):506-14
pubmed: 25251399
PLoS One. 2011;6(12):e29427
pubmed: 22216278
Int J Mol Sci. 2019 Jul 27;20(15):
pubmed: 31357595
JGH Open. 2018 Oct 17;3(1):17-24
pubmed: 30834336
Int J Clin Exp Pathol. 2015 Aug 01;8(8):9543-51
pubmed: 26464717
J Hepatol. 2012 Apr;56(4):908-43
pubmed: 22424438
Gastroenterology. 2015 Mar;148(3):547-55
pubmed: 25461851
J Mol Med (Berl). 2008 Nov;86(11):1233-41
pubmed: 18649068
Oncogene. 2002 May 2;21(19):3050-7
pubmed: 12082536
J Hepatol. 2021 Apr;74(4):775-782
pubmed: 33248170
Biochem Biophys Res Commun. 2008 Nov 14;376(2):395-8
pubmed: 18793611
Int J Mol Sci. 2018 Dec 10;19(12):
pubmed: 30544653
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Circ Res. 2015 Feb 27;116(5):789-96
pubmed: 25593281
Cancer Med. 2017 Aug;6(8):1930-1940
pubmed: 28677271
Gastroenterology. 2016 Jun;150(8):1778-85
pubmed: 26980624
Oncogene. 2007 Jul 26;26(34):4928-40
pubmed: 17310996
Hum Mol Genet. 2013 Jul 15;22(14):2941-7
pubmed: 23535823
Cell Metab. 2010 Sep 8;12(3):213-23
pubmed: 20816088
Atherosclerosis. 2010 Apr;209(2):492-7
pubmed: 19837406
PLoS Genet. 2011 May;7(5):e1002078
pubmed: 21637794
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Nat Genet. 2008 Feb;40(2):189-97
pubmed: 18193044
BMC Cardiovasc Disord. 2012 Oct 16;12:90
pubmed: 23067240
J Biol Chem. 2015 May 1;290(18):11526-36
pubmed: 25805502
J Hepatol. 2015 Sep;63(3):705-12
pubmed: 25980762
PLoS One. 2012;7(5):e37056
pubmed: 22623978
PLoS One. 2018 Jan 31;13(1):e0185490
pubmed: 29385134