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

The Pharmacogenomics Journal ARTICLE www.nature.com/tpj OPEN A potential association of SLC2A9 variant rs7442295 with uric acid at baseline and in interaction with iloperidone ✉ Sandra P. Smieszek 1,2 , Sean R. Chadwick 1,2, Emily L. Czeisler1, Rosarelis Torres1, Haimeng Bai Christos M. Polymeropoulos1, Gunther Birznieks1 and Mihael H. Polymeropoulos1 1 , Changfu Xiao1, 1234567890();,: © The Author(s) 2026 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. The Pharmacogenomics Journal (2026)26:10 ; https://doi.org/10.1038/s41397-026-00402-8 INTRODUCTION Uric acid is the end product of purine metabolism in humans and primates, who lack the enzyme uricase to further oxidize the heterocyclic compound. Under normal conditions the urate anion is generated after breakdown of excess purine nucleosides in the liver and the majority of this moiety is then excreted through the kidneys via urine. Circulating levels of uric acid the blood (i.e., blood uric acid or serum urate) correlate with disease states including high blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease [1]. Accordingly, serum uric acid testing is routinely conducted in clinical settings where the practice facilitates diagnosis of hyperuricemia, renal or kidney impairment, and rare inherited conditions [2]. The concentration of serum urate in an individual is influenced by multiple overlapping factors, including diet, medications, and genetic polymorphisms. For example, mutations identified in renal solute transporters have been identified as a major contributor to an individual’s baseline serum urate levels due to loss or gain of function in uric acid reabsorption [3, 4], whereas anti-tubercular drugs such as pyrazinamide increase reabsorption while decreasing secretion of uric acid, which can cause hyperuricemia and gout [5]. Several pharmacological interventions have been linked to clinically relevant changes in serum urate, for instance, use of low- dose acetylsalicylic acid (aspirin) on two consecutive days is associated with an increased risk of recurrent gout attacks [6]. In another example, diuretics, particularly of the thiazide class, are associated with an increase in serum urate levels, despite being indicated for treatment of hypertension [6]. These drug interactions represent direct mechanisms through which transport of uric acid can be impacted by drug interactions with various transporters and have led to inclusions of warnings and recommendations in physician prescribing guidelines regarding those drug’s risks for hyperuricemia and gout during treatment. One critical player mediating circulating levels of uric acid is the integral membrane protein GLUT9, a high-capacity hexose-urate transporter encoded by the gene SLC2A9. GLUT9 is primarily expressed in the basolateral membrane kidneys, where it mediates reabsorption of uric acid from the proximal tubule into the bloodstream [7]. Genome-wide association studies previously identified associations between SLC2A9 and serum urate concentrations [8], including loss of function variants in SLC2A9 associated with elevated levels of serum urate [9]. Access to commercial genetic testing has consistently expanded, facilitating diagnosis of renal pathology in clinical settings [10], including for SLC2A9 variants associated with hyperuricemia [11]. Accordingly, understanding iatrogenic hyperuricemia in the context of such 1 Vanda Pharmaceuticals, Inc., Washington, DC 20037, USA. 2These authors contributed equally: Sandra P. Smieszek, Sean R. Chadwick. ✉email: Received: 13 May 2024 Revised: 16 December 2025 Accepted: 3 March 2026 S.P. Smieszek et al. 2 polymorphisms in these transporters can enable health care providers to tailor treatment to individual patients and improve outcomes through precision medicine. Iloperidone is an antipsychotic medication approved by the FDA for the treatment of schizophrenia in 2009. Previous reports have documented increases in serum urate levels following treatment with drugs of the same pharmacological class, including olanzapine [12–14] and risperidone [15]. Here, we report analyses of blood uric acid concentrations obtained as part of routine clinical laboratory evaluations in two large, blinded, phase 3, randomized clinical trials of iloperidone treatment in two psychiatric patient populations (schizophrenia and bipolar mania, refer to Cutler et. al. 2008 [16] and Torres et. al. 2024 [17]). Iloperidone was associated with increases in serum urate compared to placebo or active comparator treatments in both studies. This observation led to investigation of genetic associations for this phenomenon and revealed iloperidone associated increases in serum urate are greatest in patients who were homozygous (GG) for the rs7442295 (G) allele at the SLC2A9 gene. In particular, iloperidone treated male patients with the GG genotype were observed to have serum urate concentrations above the upper limit of normal at study endpoint more frequently compared placebo group. Ultimately, these results support sex and rs7442295 genotype can be used define subgroups of patients with differential propensities for iatrogenic elevations in serum urate (...truncated)