An Association of SLC2A9 variant rs7442295 with Uric Acid at Baseline and in Interaction with Iloperidone

Abstract

Uric acid concentrations are routinely measured during clinical laboratory evaluations, given serum urate levels correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Circulating levels of uric acid are influenced by a complex mix of intrinsic and environmental factors, including genetics, diet, and drugs. We analyzed levels of uric acid in a recent phase 3 clinical trial of patients with bipolar mania treated with 24mg/day (12mg twice daily) of the antipsychotic iloperidone or placebo. Initial results revealed iloperidone treatment was associated with increases in uric acid from baseline, consistent with a similar, previous phase 3 study of iloperidone treatment of schizophrenia in adults. Pharmacogenetic analysis examining the urate transporter SLC2A9 revealed iloperidone associated increases were linked to a genetic variant (rs7442295), correlating with both urate levels at baseline and in interaction with iloperidone vs placebo. Further investigation suggested potentially clinically relevant sex differences associated with this variant, with male GG genotype patients exhibiting more frequent shifts from above the upper limit of normal for iloperidone-treated patients in comparison to female, AG/AA, and placebo groups. A pronounced increase of 35.91 µmol/L (0.674 mg/dL) was seen in iloperidone-treated patients homozygous for the for the rs7442295 (G) allele at the SLC2A9 gene, compared to a decrease of -16.5 µmol/L in the corresponding GG placebo group. Overall, the mechanism of this iloperidone-induced increase in serum urate levels is likely due to decrease in clearance of urate through interaction with the SLC2A9 urate transporter protein.