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The ABCG2 Q141K hyperuricemia and gout associated variant illuminates the physiology of human urate excretion

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  • Kazi Mirajul Hoque

    (University of Maryland School of Medicine)

  • Eryn E. Dixon

    (University of Maryland School of Medicine)

  • Raychel M. Lewis

    (University of Maryland School of Medicine)

  • Jordyn Allan

    (University of Auckland)

  • Gregory D. Gamble

    (University of Auckland)

  • Amanda J. Phipps-Green

    (University of Otago)

  • Victoria L. Halperin Kuhns

    (University of Maryland School of Medicine)

  • Anne M. Horne

    (University of Auckland)

  • Lisa K. Stamp

    (University of Otago)

  • Tony R. Merriman

    (University of Otago)

  • Nicola Dalbeth

    (University of Auckland)

  • Owen M. Woodward

    (University of Maryland School of Medicine)

Abstract

The pathophysiological nature of the common ABCG2 gout and hyperuricemia associated variant Q141K (rs2231142) remains undefined. Here, we use a human interventional cohort study (ACTRN12615001302549) to understand the physiological role of ABCG2 and find that participants with the Q141K ABCG2 variant display elevated serum urate, unaltered FEUA, and significant evidence of reduced extra-renal urate excretion. We explore mechanisms by generating a mouse model of the orthologous Q140K Abcg2 variant and find male mice have significant hyperuricemia and metabolic alterations, but only subtle alterations of renal urate excretion and ABCG2 abundance. By contrast, these mice display a severe defect in ABCG2 abundance and function in the intestinal tract. These results suggest a tissue specific pathobiology of the Q141K variant, support an important role for ABCG2 in urate excretion in both the human kidney and intestinal tract, and provide insight into the importance of intestinal urate excretion for serum urate homeostasis.

Suggested Citation

  • Kazi Mirajul Hoque & Eryn E. Dixon & Raychel M. Lewis & Jordyn Allan & Gregory D. Gamble & Amanda J. Phipps-Green & Victoria L. Halperin Kuhns & Anne M. Horne & Lisa K. Stamp & Tony R. Merriman & Nico, 2020. "The ABCG2 Q141K hyperuricemia and gout associated variant illuminates the physiology of human urate excretion," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16525-w
    DOI: 10.1038/s41467-020-16525-w
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    Cited by:

    1. Maria Pallayova & Marek Brenisin & Alina Putrya & Martin Vrsko & Sylvia Drazilova & Martin Janicko & Maria Marekova & Daniel Pella & Andrea Madarasova Geckova & Peter Urdzik & Peter Jarcuska & HepaMet, 2020. "Roma Ethnicity and Sex-Specific Associations of Serum Uric Acid with Cardiometabolic and Hepatorenal Health Factors in Eastern Slovakian Population: The HepaMeta Study," IJERPH, MDPI, vol. 17(20), pages 1-15, October.
    2. Adrienne Tin & Pascal Schlosser & Pamela R. Matias-Garcia & Chris H. L. Thio & Roby Joehanes & Hongbo Liu & Zhi Yu & Antoine Weihs & Anselm Hoppmann & Franziska Grundner-Culemann & Josine L. Min & Vic, 2021. "Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus," Nature Communications, Nature, vol. 12(1), pages 1-18, December.

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