A potential association of SLC2A9 variant rs7442295 with uric acid at baseline and in interaction with iloperidone

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 24 mg/day of the antipsychotic iloperidone or placebo. Initial results revealed that iloperidone treatment was associated with increases in uric acid from baseline (LS mean change (SE) of 27.2 (-4.93) μmol/L, compared with a change of 0.1 (-4.77) μmol/L for placebo group (LS mean difference (95% CI) = 27.1 (14.94, 39.20), p = <0.0001). Similar results were further observed in a previous phase 3 study of iloperidone treatment of schizophrenia. Pharmacogenetic analysis examining the urate transporter SLC2A9 revealed that iloperidone associated increases were linked to a genetic variant (rs7442295), correlating with both urate levels at baseline and in interaction with iloperidone vs placebo, and a pronounced increase of 35.9 μmol/L (0.67 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 (0.31 μmol/L in the corresponding GG placebo group (LS mean difference (95% CI) = 40.79 (14.61, 66.96, p = 0.0024). Further investigation suggested potentially clinically relevant sex differences associated with this variant. Specifically, 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. 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. These results may hold clinical significance for patients treated with iloperidone.