NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects

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Sliz , E , Sebert , S , Würtz , P , Kangas , A J , Soininen , P , Lehtimäki , T , Kähönen , M , Viikari , J , Männikkö , M , Ala-Korpela , M , Raitakari , O T & Kettunen , J 2018 , ' NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects ' , Human Molecular Genetics , vol. 27 , no. 12 , pp. 2214-2223 . https://doi.org/10.1093/hmg/ddy124

Title: NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects
Author: Sliz, Eeva; Sebert, Sylvain; Würtz, Peter; Kangas, Antti J.; Soininen, Pasi; Lehtimäki, Terho; Kähönen, Mika; Viikari, Jorma; Männikkö, Minna; Ala-Korpela, Mika; Raitakari, Olli T.; Kettunen, Johannes
Other contributor: University of Helsinki, Research Programs Unit


Date: 2018-06-15
Language: eng
Number of pages: 10
Belongs to series: Human Molecular Genetics
ISSN: 0964-6906
DOI: https://doi.org/10.1093/hmg/ddy124
URI: http://hdl.handle.net/10138/236757
Abstract: Fatty liver has been associated with unfavourable metabolic changes in circulation. To provide insights in fatty liver-related metabolic deviations, we compared metabolic association profile of fatty liver versus metabolic association profiles of genotypes increasing the risk of non-alcoholic fatty liver disease (NAFLD). The cross-sectional associations of ultrasound-ascertained fatty liver with 123 metabolic measures were determined in 1810 (N-fatty liver = 338) individuals aged 34-49 years from The Cardiovascular Risk in Young Finns Study. The association profiles of NAFLD-risk alleles in PNPLA3, TM6SF2, GCKR, and LYPLAL1 with the corresponding metabolic measures were obtained from a publicly available metabolomics GWAS including up to 24 925 Europeans. The risk alleles showed different metabolic effects: PNPLA3 rs738409-G, the strongest genetic NAFLD risk factor, did not associate with metabolic changes. Metabolic effects of GCKR rs1260326-T were comparable in many respects to the fatty liver associations. Metabolic effects of LYPLAL1 rs12137855-C were similar, but statistically less robust, to the effects of GCKR rs1260326-T. TM6SF2 rs58542926-T displayed opposite metabolic effects when compared with the fatty liver associations. The metabolic effects of the risk alleles highlight heterogeneity of the molecular pathways leading to fatty liver and suggest that the fatty liver-related changes in the circulating lipids and metabolites may vary depending on the underlying pathophysiological mechanism. Despite the robust cross-sectional associations on population level, the present results showing neutral or cardioprotective metabolic effects for some of the NAFLD risk alleles advocate that hepatic lipid accumulation by itself may not increase the level of circulating lipids or other metabolites.
Subject: FATTY LIVER-DISEASE
CIRCULATING TRIACYLGLYCEROL SIGNATURES
MAGNETIC-RESONANCE METABOLOMICS
EXOME-WIDE ASSOCIATION
TYPE-2 DIABETES RISK
HEPATIC STEATOSIS
NONALCOHOLIC STEATOHEPATITIS
CONFERS SUSCEPTIBILITY
TRIGLYCERIDE LEVELS
INSULIN-RESISTANCE
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
1184 Genetics, developmental biology, physiology
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