期刊
HUMAN MOLECULAR GENETICS
卷 27, 期 12, 页码 2214-2223出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddy124
关键词
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资金
- University of Oulu Graduate School
- Biocenter Oulu
- European Commission [DynaHEALTH-H2020-633595]
- Academy of Finland [283045, 297338, 307247, 312476, 312477, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071]
- Novo Nordisk Foundation [NNF17OC0026062]
- Sigrid Juselius Foundation
- University of Bristol
- UK Medical Research Council [MC_UU_12013/1]
- Tampere and Turku University Hospitals [X51001]
- 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
- Yrjo Jahnsson Foundation
- Signe and Ane Gyllenberg Foundation
- Diabetes Research Foundation of Finnish Diabetes Association
- Novo Nordisk Foundation
- MRC [MC_UU_12013/1] Funding Source: UKRI
- Academy of Finland (AKA) [312477, 297338, 307247, 312476, 307247, 297338, 312477, 312476] Funding Source: Academy of Finland (AKA)
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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