A1 Refereed original research article in a scientific journal

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




AuthorsSliz E, Sebert S, Wurtz P, Kangas AJ, Soininen P, Lehtimaki T, Kahonen M, Viikari J, Mannikko M, Ala-Korpela M, Raitakari OT, Kettunen J

PublisherOXFORD UNIV PRESS

Publication year2018

JournalHuman Molecular Genetics

Journal name in sourceHUMAN MOLECULAR GENETICS

Journal acronymHUM MOL GENET

Volume27

Issue12

First page 2214

Last page2223

Number of pages10

ISSN0964-6906

eISSN1460-2083

DOIhttps://doi.org/10.1093/hmg/ddy124

Web address https://academic.oup.com/hmg/article/27/12/2214/4966855

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/35444336


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.

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