Selenium metabolism to the trimethylselenonium ion (TMSe) varies markedly because of polymorphisms in the indolethylamine N-methyltransferase gene

Abstract

Background: Selenium is an essential element, but its metabolism in humans is not well characterized. A few small studies indicate that the trimethylselenonium ion (TMSe) is a common selenium metabolite in humans.Objective: This study aimed to elucidate the human metabolism of selenium to TMSe. Design: Study individuals constituted subsamples of 2 cohorts: 1) pregnant women (n = 228) and their 5-y-old children (n = 205) in rural Bangladesh with poor selenium status [median urinary selenium (U-Se): 6.4 mg/L in mothers, 14 mg/L in children] and 2) women in the Argentinian Andes (n = 83) with adequate selenium status (median U-Se: 24 mg/L). Total U-Se and blood selenium were measured by inductively coupled plasma mass spectrometry (ICPMS), and urinary concentrations of TMSe were measured by high-performance liquid chromatography/vapor generation/ICPMS. A genomewide association study (GWAS) was performed for 1,629,299 (after filtration) single nucleotide polymorphisms (SNPs) in the Bangladeshi women (n = 72) by using Illumina Omni5M, and results were validated by using real-time polymerase chain reaction. Results: TMSe "producers" were prevalent (approximately onethird) among the Bangladeshi women and their children, in whom TMSe constituted w10-70% of U-Se, whereas "nonproducers" had, on average, 0.59% TMSe. The TMSe-producing women had, on average, 2-mg U-Se/L higher concentrations than did the nonproducers. In contrast, only 3 of the 83 Andean women were TMSe producers (6-15% TMSe in the urine); the average percentage among the nonproducers was 0.35%. Comparison of the percentage of urinary TMSe in mothers and children indicated a strong genetic influence. The GWAS identified 3 SNPs in the indolethylamine Nmethyltransferase gene (INMT) that were strongly associated with percentage of TMSe (P , 0.001, false-discovery rate corrected) in both cohorts. Conclusions: There are remarkable population and individual variations in the formation of TMSe, which could largely be explained by SNPs in INMT. The TMSe-producing women had higher U-Se concentrations than did nonproducers, but further elucidation of the metabolic pathways of selenium is essential for the understanding of its role in human health. The MINIMat trial was registered at isrctn.org as ISRCTN16581394.Am J Clin Nutr 2015;102:1406-15.

The Association between the Urinary Excretion of Trimethylselenonium and Trimethylsulfonium in Humans

“…This gives at least a 10-fold gap in the levels between the two groups and the difference between the average levels of TMSe between the two groups was estimated to be at least 30-fold (Table 2). This variation in TMSe urinary levels is in accordance with that previously reported [5–8]. …”

“…One group, the “TMSe producers” generally excrete about 10–20% of their urinary selenium as TMSe [5–8], whereas for the second group, “TMSe non-producers”, this value is ≤1% [5,6,8]. In the present study, TMSe was detected (LOD = 0.8 nM) in the TMSe non-producers group but the levels always fell below the limit of quantification (LOQ = 2.6 nM).…”

“…A recent genome-wide association study revealed the association between TMSe production and three polymorphisms [8]. Since the three polymorphisms are in perfect linkage disequilibrium (R 2 = 1), it is not clear whether one or more of them are responsible for the variability in TMSe production.…”

“…In 2015, a genome wide association study addressed the production of TMSe in humans [8], with the identification of 3 single nucleotide polymorphisms in the indole-ethylamine N-methyltransferase ( INMT ) gene that were shown to be clearly associated with TMSe urinary levels and explained the inter-individual variability in TMSe production commonly observed in the previous studies. The reported polymorphisms were in perfect linkage disequilibrium (R 2 = 1), and included 2 polymorphisms in the 3′ untranslated region of INMT and one coding non-synonymous polymorphism (rs4720015, phenylalanine→cysteine exchange at codon 253/254) that falls outside the active site of the enzyme, but was predicted to affect protein structure based on in silico analyses [8].…”

“…The reported polymorphisms were in perfect linkage disequilibrium (R 2 = 1), and included 2 polymorphisms in the 3′ untranslated region of INMT and one coding non-synonymous polymorphism (rs4720015, phenylalanine→cysteine exchange at codon 253/254) that falls outside the active site of the enzyme, but was predicted to affect protein structure based on in silico analyses [8]. Therefore, it is not clear whether these polymorphisms affect substrate specificity: do they affect only the selenium compound or do they impart general enzymatic activity and thereby affect the production of all the enzyme products?…”