Abstract
A glutamate-to-lysine variant (rs58542926-T) in transmembrane 6 superfamily member 2 (TM6SF2) is associated with increased fatty liver disease and diabetes in conjunction with decreased cardiovascular disease risk. To identify mediators of the effects of TM6SF2, we tested for associations between rs58542926-T and serum lipoprotein/metabolite measures in cross-sectional data from nondiabetic statin-naïve participants. We identified independent associations between rs58542926-T and apoB-100 particles (β = -0.057 g/l, P = 1.99 × 10-14) and tyrosine levels (β = 0.0020 mmol/l, P = 1.10 × 10-8), controlling for potential confounders, in 6,929 Finnish men. The association between rs58542926-T and apoB-100 was confirmed in an independent sample of 2,196 Finnish individuals from the FINRISK study (βreplication = -0.029, Preplication = 0.029). Secondary analyses demonstrated an rs58542926-T dose-dependent decrease in particle concentration, cholesterol, and triglyceride (TG) content for VLDL and LDL particles (P < 0.001 for all). No significant associations between rs58542926-T and HDL measures were observed. TM6SF2 SNP rs58542926-T and tyrosine levels were associated with increased incident T2D risk in both METSIM and FINRISK. Decreased liver production/secretion of VLDL, decreased cholesterol and TGs in VLDL/LDL particles in serum, and increased tyrosine levels identify possible mechanisms by which rs58542926-T exerts its effects on increasing risk of fatty liver disease, decreasing cardiovascular disease, and increasing diabetes risk, respectively.
Highlights
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; and National Institute for Health and Welfare,§§§ Helsinki, Finland
Knockdown of tm6sf2 expression in mouse liver has been causally linked to increased hepatic steatosis [10] and rs58542926 has since been associated with a wide spectrum of liver disease [31,32,33]
To help elucidate its mechanism of action, we aimed to identify metabolites associated with the transmembrane 6 superfamily member 2 (TM6SF2) p.Glu167Lys missense variant
Summary
We identified independent associations between rs58542926-T and apoB-100 particles ( = 0.057 g/l, P = 1.99 × 10 14) and tyrosine levels ( = 0.0020 mmol/l, P = 1.10 × 10 8), controlling for potential confounders, in 6,929 Finnish men. Decreased liver production/secretion of VLDL, decreased cholesterol and TGs in VLDL/LDL particles in serum, and increased tyrosine levels identify possible mechanisms by which rs58542926-T exerts its effects on increasing risk of fatty liver disease, decreasing cardiovascular disease, and increasing diabetes risk, respectively.—Kim, D. Novel association of TM6SF2 rs58542926 genotype with increased serum tyrosine levels and decreased apoB-100 particles in Finns.
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