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

Rheumatol Int. 2017 Mar;37(3):445-453. doi: 10.1007/s00296-016-3592-2. Epub 2016 Oct 31.

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.

Keywords: Gout; Pharmacogenomics; Xanthine oxidase inhibitor.

MeSH terms

  • Acute Disease
  • Aged
  • Allopurinol / administration & dosage
  • Allopurinol / metabolism*
  • Cohort Studies
  • Febuxostat / administration & dosage
  • Febuxostat / metabolism*
  • Female
  • Gout / drug therapy
  • Gout / genetics*
  • Gout / metabolism
  • Gout Suppressants / administration & dosage
  • Gout Suppressants / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Sequence Analysis, DNA
  • Uric Acid / blood*
  • Uric Acid / metabolism
  • Xanthine Oxidase / antagonists & inhibitors*

Substances

  • Gout Suppressants
  • Febuxostat
  • Uric Acid
  • Allopurinol
  • Xanthine Oxidase