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

FinMetSeq Investigators

Research output: Contribution to journalArticle (Academic Journal)peer-review

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1471-1481
Number of pages11
JournalJournal of Lipid Research
Volume58
Issue number7
DOIs
Publication statusPublished - 24 May 2017

Keywords

  • Apolipoprotein B-100/blood
  • Cross-Sectional Studies
  • Female
  • Finland
  • Genotype
  • Humans
  • Male
  • Membrane Proteins/genetics
  • Middle Aged
  • Mutation
  • Polymorphism, Single Nucleotide
  • Tyrosine/blood

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