| 1. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 2. |
- Li, Yadi, et al.
(författare)
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Virtual and In vitro bioassay screening of phytochemical inhibitors from flavonoids and isoflavones against Xanthine oxidase and Cyclooxygenase-2 for gout treatment
- 2013
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Ingår i: Chemical Biology and Drug Design. - : John Wiley & Sons. - 1747-0277 .- 1747-0285. ; 81:4, s. 537-544
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Tidskriftsartikel (refereegranskat)abstract
- Synthetic drugs such as allopurinol and benzbroarone are commonly used to treat the complex pathogenesis of gout, a metabolic disease that results from an inflammation of the joints caused by precipitation of uric acid. We seek to discover novel phytochemicals that could treat gout, by targeting the xanthine oxidase (XO) and cyclooxygenase 2 (COX-2) enzymes. In this study, we report the screening of 9 compounds of flavonoids from the ZINC and PubChem databases (containing 2,092 flavonoids) using the iGEMDOCK software tool against the XO and COX-2 3D protein structures. Each compound was also evaluated by an in vitro bioassay testing the inhibition of XO and COX-2. Myricetin and luteolin were found to be the potential dual inhibitors of XO and COX-2 as demonstrated by IC50: 62.7 and 3.29μg/mL (XO) / 70.8 and 16.38μg/mL (COX-2), respectively. In addition, structure activity relationships and other important factors of the flavonoids binding to the active site of XO and COX-2 were discussed, which is expected for further rational drug design.
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| 3. |
- Schlosser, Pascal, et al.
(författare)
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Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine
- 2023
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Ingår i: Nature Genetics. - 1546-1718. ; 55:6, s. 995-1008
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Tidskriftsartikel (refereegranskat)abstract
- The kidneys operate at the interface of plasma and urine by clearing molecular waste products while retaining valuable solutes. Genetic studies of paired plasma and urine metabolomes may identify underlying processes. We conducted genome-wide studies of 1,916 plasma and urine metabolites and detected 1,299 significant associations. Associations with 40% of implicated metabolites would have been missed by studying plasma alone. We detected urine-specific findings that provide information about metabolite reabsorption in the kidney, such as aquaporin (AQP)-7-mediated glycerol transport, and different metabolomic footprints of kidney-expressed proteins in plasma and urine that are consistent with their localization and function, including the transporters NaDC3 (SLC13A3) and ASBT (SLC10A2). Shared genetic determinants of 7,073 metabolite-disease combinations represent a resource to better understand metabolic diseases and revealed connections of dipeptidase 1 with circulating digestive enzymes and with hypertension. Extending genetic studies of the metabolome beyond plasma yields unique insights into processes at the interface of body compartments.
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