title: 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.
  
  
  METHODS
  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 μg/L in mothers, 14 μg/L in children] and 2) women in the Argentinian Andes (n = 83) with adequate selenium status (median U-Se: 24 μg/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 one-third) among the Bangladeshi women and their children, in whom TMSe constituted ∼10-70% of U-Se, whereas "nonproducers" had, on average, 0.59% TMSe. The TMSe-producing women had, on average, 2-μg 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 N-methyltransferase 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.
authors.affiliation: Institute of Chemistry, Analytical Chemistry, NAWI Graz, University of Graz, Graz, Austria;
authors.forename: Doris
authors.initials: D
authors.lastname: Kuehnelt
authors.affiliation: Section of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden;
authors.forename: Karin
authors.initials: K
authors.lastname: Engström
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Helena
authors.initials: H
authors.lastname: Skröder
authors.affiliation: Institute of Chemistry, Analytical Chemistry, NAWI Graz, University of Graz, Graz, Austria;
authors.forename: Sabine
authors.initials: S
authors.lastname: Kokarnig
authors.affiliation: Department of Evolutionary Biology, Evolutionary Biology Center, Uppsala University, Uppsala, Sweden.
authors.forename: Carina
authors.initials: C
authors.lastname: Schlebusch
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Kippler
authors.affiliation: Section of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden;
authors.forename: Ayman
authors.initials: A
authors.lastname: Alhamdow
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Barbro
authors.initials: B
authors.lastname: Nermell
authors.affiliation: Institute of Chemistry, Analytical Chemistry, NAWI Graz, University of Graz, Graz, Austria;
authors.forename: Kevin
authors.initials: K
authors.lastname: Francesconi
authors.affiliation: Section of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and karin.broberg@ki.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Broberg
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Marie
authors.initials: M
authors.lastname: Vahter
mesh_terms: D000328:Adult; D001118:Argentina; D001459:Bangladesh; D002664:Child Nutritional Physiological Phenomena; D002675:Child, Preschool; D015331:Cohort Studies; D003677:Deficiency Diseases / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000652:urine; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D009752:Nutritional Status; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000652:urine; D065667:Renal Elimination; D012423:Rural Health; D012643:Selenium / Q000097:blood / Q000172:deficiency / Q000378:metabolism* / Q000652:urine; D018036:Selenium Compounds / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: D007527:Isoenzymes; D018036:Selenium Compounds; D008780:Methyltransferases; C033552:tryptamine N-methyltransferase; D012643:Selenium; C003717:trimethylselenonium
keywords: child; essential; excretion; human urine; metabolite; methylation; population differences; rs1061644; rs4270015; rs6970396; selenium