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Genomic sequencing of uric acid metabolizing and clearing genes in relationship to xanthine oxidase inhibitor dose

  • Genes and Disease
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Abstract

It remains unclear why the dose of xanthine oxidase inhibitors (XOI) allopurinol or febuxostat varies among patients though they reach similar serum uric acid (SUA) goal. We pursued genomic sequencing of XOI metabolism and clearance genes to identify single-nucleotide polymorphisms (SNPs) relate to differences in XOI dose. Subjects with a diagnosis of Gout based on the 1977 American College of Rheumatology Classification Criteria for the disorder, who were on stable doses of a XOI, and who were at their goal SUA level, were enrolled. The primary outcome was relationship between SNPs in any of these genes to XOI dose. The secondary outcome was relationship between SNPs and change in pre- and post-treatment SUA. We enrolled 100 subjects. The average patient age was 68.6 ± 10.6 years old. Over 80% were men and 77% were Caucasian. One SNP was associated with a higher XOI dose: rs75995567 (p = 0.031). Two SNPs were associated with 300 mg daily of allopurinol: rs11678615 (p = 0.022) and rs3731722 on Aldehyde Oxidase (AO) (His1297Arg) (p = 0.001). Two SNPs were associated with a lower dose of allopurinol: rs1884725 (p = 0.033) and rs34650714 (p = 0.006). For the secondary outcome, rs13415401 was the only SNP related to a smaller mean SUA change. Ten SNPs were identified with a larger change in SUA. Though multiple SNPs were identified in the primary and secondary outcomes of this study, rs3731722 is known to alter catalytic function for some aldehyde oxidase substrates.

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Funding

This study was funded by and the work reported herein was performed under United States Air Force Surgeon General-approved Clinical Investigation FKE20120020H.

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Authors and Affiliations

  1. Keesler AFB, 301 Fisher Avenue, Biloxi, MS, 39534, USA

    Matthew B. Carroll & Thomas L. Shaak

  2. Lackland AFB, 2200 Bergquist Drive, Ste 1, San Antonio, TX, 78236, USA

    Derek M. Smith

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  1. Matthew B. Carroll
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Correspondence to Matthew B. Carroll.

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Conflict of interest

Author Carroll, MB declares that he has no conflict of interest. Author Smith, DM declares that he has no conflict of interest. Author Shaak, T declares that he has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

The voluntary, fully informed consent of the subjects used in this research was obtained as required by 32 CFR 219 and AFI 40-402, Protection of Human Subjects in Biomedical and Behavioral Research. Informed consent was obtained from all individual participants included in the study.

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The views expressed in this article are those of the authors and do not reflect the official policy or position of the United States Air Force, Department of Defense, or the US Government.

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Carroll, M.B., Smith, D.M. & Shaak, T.L. Genomic sequencing of uric acid metabolizing and clearing genes in relationship to xanthine oxidase inhibitor dose. Rheumatol Int 37, 445–453 (2017). https://doi.org/10.1007/s00296-016-3592-2

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  • DOI: https://doi.org/10.1007/s00296-016-3592-2

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