Sources of variation of transthyretin in healthy subjects in East and Southeast Asia: Clinical and experimental evidence for the effect of alcohol on transthyretin metabolism

• The sources of variation of serum TTR levels were determined in 3511 healthy individuals for common reference intervals.
• Sex, aging, BMI, and especially the level of daily alcohol consumption may be factors affecting serum TTR concentrations.
• Ethanol treatment induced TTR expression, at least in part, via a mechanism dependent of HNF-4 α.
• Sources of variation analyses revealed the clinical significance of TTR as reliable clinical biomarkers.

BackgroundAlthough transthyretin (TTR), a negative acute phase protein, is recognized as one of the nutrition assessment proteins, factors affecting serum TTR concentrations than nutritional state in healthy subjects have not been well understood. We investigated the sources of variation of serum TTR concentrations in healthy subjects.MethodsSerum samples of 3511 healthy volunteers (2055 of Japanese subjects and 1456 of other East and Southeast Asian subjects) were collected. We measured serum TTR concentrations in addition to routine blood examinations in each sample, and assessed the relationship between each serum TTR concentrations and the clinical indices such as age, sex, body mass index (BMI), smoking, and level of daily alcohol consumption. We also investigated the direct alcohol effect of TTR expression by assessing TTR mRNA and protein levels in vivo and in vitro experiments.ResultsMean TTR concentrations of males were prominently higher than those of females. Multiple regression analysis revealed that serum TTR concentrations increased with age, BMI, and the level of daily alcohol consumption after adjustment for a slight regional difference. Moreover, TTR expression was up-regulated by alcohol treatment through hepatocyte nuclear factor 4α (HNF-4α) in vitro and in vivo experiments.ConclusionsSex, aging, BMI, and the level of daily alcohol consumption may be the factors affecting serum TTR concentrations in healthy subjects.