Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Effective long term uric acid lowering therapy with the xanthine oxidase inhibitors (XOI) allopurinol and febuxostat exists. When compliant with therapy, it is unclear why some patients need higher or lower doses of XOI yet achieve the same serum uric acid (SUA) goal. We pursued genomic sequencing (GS) of genes related to XOI metabolism and clearance to determine if any SNVs relate to differences in dose needed.
Methods: 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. When available up to 3 pre- and post-treatment SUA values were recorded. GS was performed on whole blood samples for genes related to metabolism of allopurinol, specifically XO, aldehyde oxidase 1 (AOX1), and molybdenum cofactor sulfurase (MOCOS). The gene SLC22A12 was sequenced because it impacts oxypurinol clearance. For the metabolism of febuxostat, the genes uridine diphosphate glucuronsyltransferase (UDT) 1A1 and 1A4 were sequenced. The primary outcome was to detect any relationship between single nucleotide variants (SNVs) in any of these genes to XOI dose. The secondary outcome was to detect a relationship between SNVs and change in SUA, specifically the difference between average pre- and post-treatment values.
Results: Time and funding permitted sequencing of our first 80 subjects. The average patient age was 68.3 ± 11.2 years old. The majority were men and 76% were Caucasian. The GS error rate was 0.293 ± 0.048%. Of 1.8 ± 0.5 million base pairs mapped, 145 SNVs were identified; no indels were identified. For the primary outcome, 5 SNVs were associated with a lower XOI dose (allopurinol ≤ 300 mg daily) to reach a goal SUA (all p < 0.05): rs13419410, rs6760292, rs34929837, rs45612738, and rs4541294. One SNV, rs7599556 was associated with a higher XOI dose (allopurinol > 300 mg daily) to reach a goal SUA. Of these SNVs, rs34929837 is an exonic missense mutation affecting XO (Lys395Met) and lies in the Flavin adenine nucleotide (FAD) domain of the enzyme. Rs45612738 is a synonymous codon in XO (Gly378=). All other SNVs were intronic with the majority in XO. For the secondary outcome, 1 SNV was associated with a smaller change in SUA with a lower XOI dose: rs6760292 (p < 0.05). This SNV is intronic and located in XO. Four SNVs were associated with larger changes in SUA with febuxostat 80 mg daily (all p < 0.05): rs7599556, rs75995567, rs145877467, and rs78467837. Both rs145877467 and rs78467837 are synonymous codons in AOX1(Pro1245= and Ser1264= respectively).
Conclusion: Though the sample size is modest, we identified multiple SNVs that were associated with a lower XOI dose and one related to a higher XOI dose to reach a goal SUA. One of the exonic alleles detected, rs34929837, leads to an amino acid substitution in the FAD co-factor domain of xanthine oxidase. Additional work is needed to assess the impact of this change but our data may start to explain why some patients need different doses of XOI and yet achieve the same serum uric acid (SUA) goal.
To cite this abstract in AMA style:Carroll M, Cook K, Shaak T. Genomic Sequencing of Uric Acid Metabolizing and Clearing Genes in Relationship to Xanthine Oxidase Inhibitor Dose [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/genomic-sequencing-of-uric-acid-metabolizing-and-clearing-genes-in-relationship-to-xanthine-oxidase-inhibitor-dose/. Accessed June 7, 2020.
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