Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies.
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
20
05
2019
accepted:
17
07
2019
entrez:
26
9
2019
pubmed:
26
9
2019
medline:
23
2
2020
Statut:
epublish
Résumé
Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value <1x10-30). In cells over-expressing human or various mammalian orthologs of SLC22A24, we showed that steroid conjugates and bile acids were substrates of the transporter. Phylogenetic, genomic, and transcriptomic analyses suggested that SLC22A24 has a specialized role in the kidney and appears to function in the reabsorption of organic anions, and in particular, anionic steroids. Phenome-wide analysis showed that functional variants of SLC22A24 are associated with human disease such as cardiovascular diseases and acne, which have been linked to dysregulated steroid metabolism. Collectively, these functional genomic studies reveal a previously uncharacterized protein involved in steroid homeostasis, opening up new possibilities for SLC22A24 as a pharmacological target for regulating steroid levels.
Identifiants
pubmed: 31553721
doi: 10.1371/journal.pgen.1008208
pii: PGENETICS-D-19-00821
pmc: PMC6760779
doi:
Substances chimiques
Organic Cation Transport Proteins
0
SLC22A4 protein, human
0
Steroids
0
Symporters
0
androsterone glucuronide
1852-43-3
Androsterone
C24W7J5D5R
Types de publication
Journal Article
Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008208Subventions
Organisme : NHLBI NIH HHS
ID : RC2 HL102419
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK108722
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL122508
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201700002C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201700001I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201700004I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201700003I
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG004402
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG003273
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201700005C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201700001C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201700003C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201700004C
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM117163
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201700002I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201700005I
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008898
Pays : United States
Déclaration de conflit d'intérêts
J.M.K. is employed by Metabolon Inc. Other authors have declared that no competing interests exist.
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