Novel association of TM6SF2 rs58542926 genotype with increased serum tyrosine levels and decreased apoB-100 particles in Finns

Journal of Lipid Research

Elizabeth K. Speliotes¹  Anne U. Jackson²  Pasi Soininen³  Markku Laakso⁴  Veikko Salomaa⁴  Mika Ala-Korpela⁵  Michael Boehnke⁵  Charles F. Burant⁵  Yatong K. Li⁶  Heather M. Stringham⁶  Johanna Kuusisto⁶  Antti J. Kangas⁷  Daniel Seung Kim⁸ 

[1] Computational Medicine, School of Social and Community Medicine and Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom;Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI;Department of Medicine, Kuopio University Hospital, Kuopio, Finland;Nuclear Magnetic Resonance Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland;Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland;Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI;Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland;To whom correspondence should be addressed.;

关键词: transmembrane 6 superfamily member 2;    nonalcoholic fatty liver disease;    epidemiology;    cardiovascular disease;    type 2 diabetes;    apolipoprotein B-100;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown