Renal Metabolite Handling: from Gene to Function to Disease
Epidemiology and Medical Biometry/Statistics
Human Genetics
Final Report Abstract
This research proposal aimed to identify novel candidate genes of metabolite handling via linking common and rare genetic variants to the levels of thousands of metabolites in plasma and urine. Significant association detected through such an approach represent gene metabolite pairs that implicate the encoded protein as having a role in a reaction that contains the metabolite or a related molecule. These proteins often operate as enzymes and transporters. The project progresses as planned. The approach was very successful and resulted in multiple publications. Examples of novel findings contained the discovery of several relationships between metabolite levels and genetic variants in genes encoding for orphan transporters, i.e., transporters for which physiological substrates remain elusive. Based on these studies, one successful deorphanization study was already completed and published, and additional ones are ongoing. The discovery of dozens of reactions likely taking place in the kidney and only possible by studying urine metabolites represents another milestone and constitutes a valuable resource for many experimental follow-up studies.
Publications
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Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans. Nature Genetics, 52(2), 167-176.
Schlosser, Pascal; Li, Yong; Sekula, Peggy; Raffler, Johannes; Grundner-Culemann, Franziska; Pietzner, Maik; Cheng, Yurong; Wuttke, Matthias; Steinbrenner, Inga; Schultheiss, Ulla T.; Kotsis, Fruzsina; Kacprowski, Tim; Forer, Lukas; Hausknecht, Birgit; Ekici, Arif B.; Nauck, Matthias; Völker, Uwe; Walz, Gerd ... & Köttgen, Anna
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NAT8 Variants, N-Acetylated Amino Acids, and Progression of CKD. Clinical Journal of the American Society of Nephrology, 16(1), 37-47.
Luo, Shengyuan; Surapaneni, Aditya; Zheng, Zihe; Rhee, Eugene P.; Coresh, Josef; Hung, Adriana M.; Nadkarni, Girish N.; Yu, Bing; Boerwinkle, Eric; Tin, Adrienne; Arking, Dan E.; Steinbrenner, Inga; Schlosser, Pascal; Köttgen, Anna & Grams, Morgan E.
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Urine 6-Bromotryptophan: Associations with Genetic Variants and Incident End-Stage Kidney Disease. Scientific Reports, 10(1).
Sekula, Peggy; Tin, Adrienne; Schultheiss, Ulla T.; Baid-Agrawal, Seema; Mohney, Robert P.; Steinbrenner, Inga; Yu, Bing; Luo, Shengyuan; Boerwinkle, Eric; Eckardt, Kai-Uwe; Coresh, Josef; Grams, Morgan E. & Kӧttgen, Anna
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Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism. Nature Communications, 12(1).
Cheng, Yurong; Schlosser, Pascal; Hertel, Johannes; Sekula, Peggy; Oefner, Peter J.; Spiekerkoetter, Ute; Mielke, Johanna; Freitag, Daniel F.; Schmidts, Miriam; Oefner, Peter J.; Kronenberg, Florian; Eckardt, Kai-Uwe; Kronenberg, Florian; Eckardt, Kai-Uwe; Thiele, Ines; Li, Yong & Köttgen, Anna
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Coupling of metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and resulting traits and diseases. openRxiv.
Scherer, Nora; Fässler, Daniel; Borisov, Oleg; Cheng, Yurong; Schlosser, Pascal; Wuttke, Matthias; Patil, Suraj; Meiselbach, Heike; Telkämper, Fabian; Berger, Urs; Grünert, Sarah; Sekula, Peggy; Schultheiss, Ulla T.; Li, Yong; Köttgen, Michael; Oefner, Peter J.; Knauf, Felix; Eckardt, Kai-Uwe; Thiele, Ines ... & Köttgen, Anna
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Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine. Nature Genetics, 55(6), 995-1008.
Schlosser, Pascal; Scherer, Nora; Grundner-Culemann, Franziska; Monteiro-Martins, Sara; Haug, Stefan; Steinbrenner, Inga; Uluvar, Burulça; Wuttke, Matthias; Cheng, Yurong; Ekici, Arif B.; Gyimesi, Gergely; Karoly, Edward D.; Kotsis, Fruzsina; Mielke, Johanna; Gomez, Maria F.; Yu, Bing; Grams, Morgan E.; Coresh, Josef; Boerwinkle, Eric ... & Köttgen, Anna
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The membrane transporter SLC25A48 enables transport of choline into human mitochondria. Kidney International, 107(2), 296-301.
Patil, Suraj; Borisov, Oleg; Scherer, Nora; Wirth, Christophe; Schlosser, Pascal; Wuttke, Matthias; Ehret, Sandra; Hannibal, Luciana; Eckardt, Kai-Uwe; Hunte, Carola; Neubauer, Björn; Köttgen, Anna & Köttgen, Michael
