Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans.
Acetyltransferases
/ genetics
Alkaline Phosphatase
/ genetics
Biomarkers
/ urine
Biotransformation
/ genetics
Cohort Studies
Cytochrome P-450 CYP2D6
/ genetics
Genome-Wide Association Study
Humans
Inactivation, Metabolic
Kidney
/ cytology
Metoprolol
/ pharmacokinetics
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Renal Insufficiency, Chronic
/ genetics
Urine
/ physiology
Xenobiotics
/ pharmacokinetics
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
22
02
2019
accepted:
05
12
2019
pubmed:
22
1
2020
medline:
14
4
2020
entrez:
22
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31959995
doi: 10.1038/s41588-019-0567-8
pii: 10.1038/s41588-019-0567-8
pmc: PMC7484970
mid: NIHMS1615960
doi:
Substances chimiques
Biomarkers
0
Xenobiotics
0
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Acetyltransferases
EC 2.3.1.-
NAT8 protein, human
EC 2.3.1.-
ALPL protein, human
EC 3.1.3.1
Alkaline Phosphatase
EC 3.1.3.1
Metoprolol
GEB06NHM23
Types de publication
Journal Article
Observational Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
167-176Subventions
Organisme : NIA NIH HHS
ID : RF1 AG057452
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG058942
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG059093
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061359
Pays : United States
Commentaires et corrections
Type : CommentIn
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