Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies

English version

Autoři: Sook Wah Yee ^aff001; Adrian Stecula ^aff001; Huan-Chieh Chien ^aff001; Ling Zou ^aff001; Elena V. Feofanova ^aff002; Marjolein van Borselen ^aff001; Kit Wun Kathy Cheung ^aff001; Noha A. Yousri ^aff003; Karsten Suhre ^aff005; Jason M. Kinchen ^aff006; Eric Boerwinkle ^aff002; Roshanak Irannejad ^aff008; Bing Yu ^aff002; Kathleen M. Giacomini ^aff001
Působiště autorů: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, California, United States of America ^aff001; Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America ^aff002; Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar ^aff003; Computer and Systems Engineering, Alexandria University, Alexandria, Egypt ^aff004; Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar ^aff005; Metabolon, Inc, Durham, United States of America ^aff006; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America ^aff007; The Cardiovascular Research Institute, University of California, San Francisco, California, United States of America ^aff008; Institute for Human Genetics, University of California San Francisco, California, United States of America ^aff009
Vyšlo v časopise: Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies. PLoS Genet 15(9): e32767. doi:10.1371/journal.pgen.1008208
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008208

Souhrn

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.

Klíčová slova:

Drug metabolism – Genome-wide association studies – Kidneys – Membrane proteins – Metabolomics – Steroids – Sulfates – Anions

Zdroje

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