University of Oulu

Eeva Sliz, Sylvain Sebert, Peter Würtz, Antti J Kangas, Pasi Soininen, Terho Lehtimäki, Mika Kähönen, Jorma Viikari, Minna Männikkö, Mika Ala-Korpela, Olli T Raitakari, Johannes Kettunen; NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects, Human Molecular Genetics, Volume 27, Issue 12, 15 June 2018, Pages 2214–2223,

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

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Author: Sliz, Eeva1,2; Sebert, Sylvain1,2,3; Würtz, Peter4,5;
Organizations: 1Center for Life Course Health Research, Faculty of Medicine, University of Oulu
2Biocenter Oulu, University of Oulu
3Department of Genomics of Complex Diseases, School of Public Health, Imperial College London
4Research Programs Unit, Diabetes and Obesity, University of Helsinki
5Nightingale Health Ltd.
6NMR Metabolomics Laboratory, School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland
7Fimlab Laboratories, Department of Clinical Chemistry, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Life Sciences, University of Tampere
8Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere
9Division of Medicine, Department of Medicine, University of Turku, Turku University Hospital
10Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu
11Computational Medicine, Faculty of Medicine, University of Oulu
12opulation Health Science, Bristol Medical School, University of Bristol and Medical Research Council Integrative Epidemiology Unit at the University of Bristol
13Systems Epidemiology, Baker Heart and Diabetes Institute
14Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University
15Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku
16Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital
17Population Health Science, Bristol Medical School, University of Bristol and Medical Research Council Integrative Epidemiology Unit at the University of Bristol
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.5 MB)
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Language: English
Published: Oxford University Press, 2018
Publish Date: 2018-08-15


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 (Nfatty 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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Series: Human molecular genetics
ISSN: 0964-6906
ISSN-E: 1460-2083
ISSN-L: 0964-6906
Volume: 27
Issue: 12
Pages: 2214 - 2223
DOI: 10.1093/hmg/ddy124
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This work was supported by University of Oulu Graduate School [E.S.]; Biocenter Oulu [S.S.]; European Commission [DynaHEALTH—H2020-633595, S.S.]; Academy of Finland [283045, 297338, 307247, J.K.] [312476, 312477, P.W.]; Novo Nordisk Foundation [P.W.] [NNF17OC0026062, J.K.]; Sigrid Juselius Foundation [M.A.K.]; and University of Bristol and UK Medical Research Council [MC_UU_12013/1, M.A.K.]. The Young Finns Study has been supported by Tampere and Turku University Hospitals [X51001, T.L.]; the Academy of Finland [286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), 41071 (Skidi)]; the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio; Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association. Funding to pay the Open Access publication charges for this article was provided by Novo Nordisk Foundation.
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
Academy of Finland Grant Number: 297338
Detailed Information: 297338 (Academy of Finland Funding decision)
307247 (Academy of Finland Funding decision)
Copyright information: © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact