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Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies
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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760779/ https://www.ncbi.nlm.nih.gov/pubmed/31553721 http://dx.doi.org/10.1371/journal.pgen.1008208 |
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author | Yee, Sook Wah Stecula, Adrian Chien, Huan-Chieh Zou, Ling Feofanova, Elena V. van Borselen, Marjolein Cheung, Kit Wun Kathy Yousri, Noha A. Suhre, Karsten Kinchen, Jason M. Boerwinkle, Eric Irannejad, Roshanak Yu, Bing Giacomini, Kathleen M. |
author_facet | Yee, Sook Wah Stecula, Adrian Chien, Huan-Chieh Zou, Ling Feofanova, Elena V. van Borselen, Marjolein Cheung, Kit Wun Kathy Yousri, Noha A. Suhre, Karsten Kinchen, Jason M. Boerwinkle, Eric Irannejad, Roshanak Yu, Bing Giacomini, Kathleen M. |
author_sort | Yee, Sook Wah |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6760779 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-67607792019-10-04 Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies Yee, Sook Wah Stecula, Adrian Chien, Huan-Chieh Zou, Ling Feofanova, Elena V. van Borselen, Marjolein Cheung, Kit Wun Kathy Yousri, Noha A. Suhre, Karsten Kinchen, Jason M. Boerwinkle, Eric Irannejad, Roshanak Yu, Bing Giacomini, Kathleen M. PLoS Genet Research Article 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. Public Library of Science 2019-09-25 /pmc/articles/PMC6760779/ /pubmed/31553721 http://dx.doi.org/10.1371/journal.pgen.1008208 Text en © 2019 Yee et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Yee, Sook Wah Stecula, Adrian Chien, Huan-Chieh Zou, Ling Feofanova, Elena V. van Borselen, Marjolein Cheung, Kit Wun Kathy Yousri, Noha A. Suhre, Karsten Kinchen, Jason M. Boerwinkle, Eric Irannejad, Roshanak Yu, Bing Giacomini, Kathleen M. Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies |
title | Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies |
title_full | Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies |
title_fullStr | Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies |
title_full_unstemmed | Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies |
title_short | Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies |
title_sort | unraveling the functional role of the orphan solute carrier, slc22a24 in the transport of steroid conjugates through metabolomic and genome-wide association studies |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760779/ https://www.ncbi.nlm.nih.gov/pubmed/31553721 http://dx.doi.org/10.1371/journal.pgen.1008208 |
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