title: A 'complexity' of urate transporters.
abstract: Genetic variation in the SLC2A9 gene is a new genetic risk factor for low fractional excretion of uric acid, hyperuricemia, and gout. Its gene product, GLUT9, was previously known as a type II glucose/fructose transporter but is now known to function as a high-capacity uric acid transporter that is expressed in kidney, liver, and several other tissues. Follow-up meta-analyses, including one with data from 28,141 individuals, implicated a total of nine additional loci influencing serum urate concentrations, including six other membrane transporters (SLC17A1, SLC17A3, SLC22A11, SLC22A12, SLC16A9, and ABCG2). Variants in these genes together account for about 5% of the variance in serum urate, two-thirds of which is due to SLC2A9. Using these variants in 'Mendelian randomization' analyses provides a powerful means of dissecting the role of urate in cardiovascular and metabolic diseases, where cause-and-effect influences are difficult to discern due to potential confounding. The results highlight the complex interplay of membrane transporters involved in urate metabolism. They also show how variants of weak effect identified by genome-wide association studies can still be important in identifying novel pathways, including a 'complexity' of new and potentially druggable targets for modifying urate transport.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, UK. alan.wright@hgu.mrc.ac.uk
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D055106:Genome-Wide Association Study; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000502:physiology; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000502:physiology*; D027701:Organic Cation Transport Proteins / Q000502:physiology; D014527:Uric Acid / Q000378:metabolism*; D014528:Uricosuric Agents / Q000627:therapeutic use; D058949:Uromodulin / Q000235:genetics
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D051246:Glucose Transport Proteins, Facilitative; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; C411811:SLC2A9 protein, human; C548612:UMOD protein, human; D014528:Uricosuric Agents; D058949:Uromodulin; C103862:urate transporter; D014527:Uric Acid