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      Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans

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          Abstract

          The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function. The 240 unique metabolite–locus associations (metabolite quantitative trait loci, mQTLs) that were identified and replicated highlight novel candidate substrates for transport proteins. The identified genes are enriched in ADME-relevant tissues and cell types, and they reveal novel candidates for biotransformation and detoxification reactions. Fine mapping of mQTLs and integration with single-cell gene expression permitted the prioritization of causal genes, functional variants and target cell types. The combination of mQTLs with genetic and health information from 450,000 UK Biobank participants illuminated metabolic mediators, and hence, novel urinary biomarkers of disease risk. This comprehensive resource of genetic targets and their substrates is informative for ADME processes in humans and is relevant to basic science, clinical medicine and pharmaceutical research.

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          Most cited references36

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites

            Amalio Telenti, Craig Venter and colleagues report common, low-frequency and rare variants associated with blood metabolite levels using whole-genome sequencing and comprehensive metabolite profiling in 1,960 individuals. They identify 246 metabolites whose levels are associated with genetic variation at 101 loci.
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              What do drug transporters really do?

              Potential drug-drug interactions mediated by the ATP-binding cassette (ABC) transporter and solute carrier (SLC) transporter families are of clinical and regulatory concern. However, the endogenous functions of these drug transporters are not well understood. Discussed here is evidence for the roles of ABC and SLC transporters in the handling of diverse substrates, including metabolites, antioxidants, signalling molecules, hormones, nutrients and neurotransmitters. It is suggested that these transporters may be part of a larger system of remote communication ('remote sensing and signalling') between cells, organs, body fluid compartments and perhaps even separate organisms. This broader view may help to clarify disease mechanisms, drug-metabolite interactions and drug effects relevant to diabetes, chronic kidney disease, metabolic syndrome, hypertension, gout, liver disease, neuropsychiatric disorders, inflammatory syndromes and organ injury, as well as prenatal and postnatal development.
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                Author and article information

                Journal
                Nature Genetics
                Nat Genet
                Springer Science and Business Media LLC
                1061-4036
                1546-1718
                January 20 2020
                Article
                10.1038/s41588-019-0567-8
                7484970
                31959995
                ebef776a-0e43-4c74-b340-15356c3f3764
                © 2020

                http://www.springer.com/tdm

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