Genetic variation in the INMT gene strongly impacts the production of trimethylsulfonium in humans

We previously identified the trimethylsulfonium ion (TMS) in human urine and highlighted its potential as a novel H₂S biomarker but observed significant inter-individual variability in its urinary excretion. In this work we investigate the contribution of genetic factors to this variability in a group of European subjects (n = 100) from the BioPersMed cohort. Urinary TMS concentrations displayed two clusters within 5.0-20 nM and 100-400 nM. Genotyping revealed that this clustering is linked to a single nucleotide polymorphism (rs6970396) in the INMT gene, P < 0.001. We found strong contrast in the effects of rs6970396 between TMS and the selenium analogue TMSe which is one of many other detoxification products of the poorly recognized chalcogen-methylation activity of the INMT enzyme. Genetic variability in INMT has wide implications not only for the detoxification of H₂S, both inhaled and naturally produced, but also for that of other volatile sulfur compounds in humans which may serve as substrates including xenobiotics.