Abstract
Fatty liver has been associated with unfavourable metabolic changes in circulation and is considered as a risk factor for cardiometabolic complications such as type 2 diabetes and cardiovascular disease. We aimed to provide insights in fatty liver related metabolic deviations by studying the resemblance between the metabolic profile associated with fatty liver observationally and metabolic profiles of non-alcoholic fatty liver disease (NAFLD) risk increasing genotypes. We determined cross-sectional associations of ultrasound-ascertained fatty liver status with 123 metabolic traits in 1,810 individuals aged 34-49 years from The Cardiovascular Risk in Young Finns Study. The cross-sectional associations were compared with the association profiles of NAFLD risk alleles in PNPLA3, TM6SF2, GCKR, and LYPLAL1 with the corresponding metabolic traits obtained from a publicly available genome-wide association study including up to 24,925 European individuals. The analysis revealed substantially different metabolic effects of the risk alleles. PNPLA3 rs738409-G, the strongest genetic risk factor to NAFLD, did not associate with metabolic changes. GCKR rs1260326-T resulted in an association profile similar to the observational fatty liver associations. Metabolic effects of LYPLAL1 rs12137855-C were similar, but statistically less robust, to the effects of GCKR rs1260326-T. In contrast, NAFLD risk allele TM6SF2 rs58542926-T displayed opposite metabolic associations when compared with the observational association pattern.
Conclusion The divergent effects of the risk alleles on circulating lipids and metabolites underline involvement of several metabolic pathways in NAFLD and suggest that there are pathogenically different subtypes of NAFLD with alternate metabolic consequences. NAFLD risk alleles may have neutral or even cardioprotective effect on circulating lipids and metabolites providing evidence that hepatic lipid accumulation by itself would not necessarily cause the metabolic deviations associated observationally with fatty liver.
Footnotes
Contact Information: Johannes Kettunen, Address: Faculty of Medicine, Computational Medicine, Center For Life Course Health Research, Aapistie 5A, P.O.Box 5000, 90014 University of Oulu, Oulu, Finland, Telephone: + 358 50 562 9718, E-mail: johannes.kettunen{at}computationalmedicine.fi
- List of Abbreviations
- NAFLD
- non-alcoholic fatty liver disease;
- PNPLA3
- Patatin-like phospholipase domain containing 3;
- TM6SF2
- Transmembrane 6 superfamily member 2;
- LYPLAL1
- Lysophospholipase-like 1;
- GCKR
- Glucokinase regulator;
- GWAS
- genome-wide association study;
- YFS
- Young Finns Study;
- VLDL
- very low-density lipoprotein;
- IDL
- intermediate-density lipoprotein;
- LDL
- low-density lipoprotein;
- NMR
- nuclear magnetic resonance;
- SNP
- single nucleotide polymorphism;
- FA
- fatty acid;
- TG
- triglyceride.
Financial Support: ES was funded by University of Oulu Graduate School (UniOGS). SS is thankful to the academy of Finland, Biocenter Oulu and the European commission (grant DynaHEALTH - H2020 – 633595). JK was funded through Academy of Finland (grant numbers 283045, 297338 and 307247) and Novo Nordisk Foundation (NNF17OC0026062). PW: AoF 312476 & 312477, and Novo Nordisk Foundation. MAK was supported by the Sigrid Juselius Foundation. MAK works in a Unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_12013/1). The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001 for T.L.); 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.
Disclosures: PW, AJK, and PS are employees and shareholders of Nightingale Health Ltd, a company offering NMR-based biomarker profiling.
