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Crystal arthropathies
Original article
Influence of genetic variants on renal uric acid handling in response to frusemide: an acute intervention study
  1. Nicola Dalbeth1,
  2. Jordyn Allan1,
  3. Gregory D Gamble1,
  4. Amanda Phipps-Green2,
  5. Tanya J Flynn2,
  6. Borislav Mihov1,
  7. Anne Horne1,
  8. Robert Doughty1,
  9. Lisa K Stamp3 and
  10. Tony R Merriman2
  1. 1Department of Medicine, University of Auckland, Auckland, New Zealand
  2. 2Department of Biochemistry, University of Otago, Dunedin, New Zealand
  3. 3Department of Medicine, University of Otago, Christchurch, New Zealand
  1. Correspondence to Professor Nicola Dalbeth; n.dalbeth{at}auckland.ac.nz

Abstract

Objectives Genetic variation in the renal urate transporters SLC2A9 (GLUT9) and SLC22A11 (OAT4) has been reported to interact with diuretics to increase the risk of developing gout. The aim of this study was to determine whether variation in SLC2A9 or SLC22A11 influences acute renal handling of uric acid in response to frusemide.

Methods Following an overnight fast, healthy participants (n=100) attended a study visit with oral intake of 40 mg frusemide. Blood and urine samples were obtained at baseline and 30, 60, 120 and 180 min after frusemide intake. The primary end point was change in fractional excretion of uric acid (FEUA).

Results Following intake of frusemide, FEUA initially increased (mean (SD) change from baseline +1.9% (3.0%) at 60 min, p<0.001) and then decreased (mean (SD) change from baseline −1.5% (2.1%) at 180 min, p<0.001). A very small increase in serum urate was observed over the study period (mean (SD) change from baseline 0.007 (0.01) mmol/L at 180 min, p<0.001). The presence of the urate-lowering and gout-protective alleles for SLC2A9 (rs11942223 and rs13129697) and SLC22A11 (rs207826) did not significantly alter the FEUA following a frusemide load. At both 60 and 180 min, change in fractional excretion of sodium was independently associated with change in FEUA (standardised β≥0.40, p<0.001).

Conclusions The tested variants in SLC2A9 and SLC22A11 do not influence acute changes in renal handling of uric acid in response to frusemide.

Trial registration number ACTRN12614000871640; Results.

  • Gout
  • Gene Polymorphism
  • Pharmacogenetics

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/rmdopen-2016-000424

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    Footnotes

    • Contributors ND (the guarantor) accepts full responsibility for the work and the conduct of the study, had access to the data and controlled the decision to publish. ND conceived the study, contributed to the data interpretation, and drafted the manuscript. JA and AH recruited participants, coordinated study visits and contributed to data acquisition. JA and BM managed clinical data management, AP-G and TJF contributed to data acquisition and genetic data management. GDG analysed the data. RD, LKS and TRM conceived of the study, contributed to the data interpretation and drafted the manuscript. All authors read and approved the final manuscript.

    • Funding This work was supported by the Health Research Council of New Zealand (grant number 14-527).

    • Competing interests ND reports grant funding, consultancy or speaker fees from Takeda, Teijin, Menarini, Pfizer, Ardea Biosciences/AstraZeneca, Cymabay and Crealta, all outside the submitted work. LKS reports grant funding and consultancy from Ardea Biosciences/AstraZeneca, all outside the submitted work. TRM reports grant funding and consultancy from Ardea Biosciences/AstraZeneca, all outside the submitted work.

    • Ethics approval New Zealand Ministry of Health Multiregional Ethics Committee (MEC/05/10/130/AM06).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement No additional data are available.