20.500.12556/RUL-185778 Genetic variants in purine metabolism and treatment resistance in schizophrenia a pilot study Background: The adenosine hypothesis of schizophrenia provides an integrative framework in which reduced adenosinergic signalling contributes to dopaminergic hyperactivity and glutamatergic hypofunction. Enzymes regulating purine metabolism, including inosine triphosphatase (ITPA), adenosine monophosphate deaminase 1 (AMPD1), and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), may influence adenosine availability and thereby modulate disease susceptibility and treatment response. As part of a pilot pharmacogenetic investigation, we investigated whether functional polymorphisms in these genes are associated with schizophrenia risk, treatment resistance, and symptom severity. Methods: A total of 249 patients with schizophrenia (including 47 with treatment-resistant schizophrenia - TRS) and 93 healthy controls were genotyped for ITPA rs1127354, AMPD1 rs17602729, and ATIC rs2372536 in this exploratory, hypothesis-generating study. Case-control and TRS analyses were conducted using χ2 tests and logistic regression with Bonferroni correction. Symptom severity (BPRS), global functioning (GAF), and positive and negative symptom subscales were examined using two-way ANOVA with false discovery rate (FDR) adjustment for multiple exploratory comparisons. Results: ITPA rs1127354 showed a nominally significant recessive association with schizophrenia risk based on a very small genotype count (OR = 0.09, p = 0.033), driven by rare AA homozygosity, but did not remain significant after Bonferroni correction. No significant case-control associations were observed for AMPD1 or ATIC. In contrast, ATIC rs2372536 was significantly associated with TRS (χ2 = 10.86, p = 0.004; CG vs. CC OR = 2.68, 95% CI 1.20-6.55), remaining significant after Bonferroni correction. In exploratory dimensional analyses, uncorrected genotype-related effects were observed for global functioning and overall symptom severity; after FDR adjustment, only the association between ATIC rs2372536 and negative symptoms remained statistically supported at q < 0.10. AMPD1 rs17602729 showed associations with overall symptom burden at the unadjusted level. Conclusion: Our findings provide preliminary evidence that genetic variation in purine metabolism may contribute to clinical heterogeneity in schizophrenia. In particular, ATIC rs2372536 was associated with treatment resistance and negative symptom severity, supporting a potential role of adenosinergic mechanisms in antipsychotic response. Associations with schizophrenia risk and other dimensions were exploratory and require replication in larger, independent cohorts. Integration of genetic data with biochemical measures of purine and adenosine metabolism will be important to establish clinical relevance and support precision-oriented therapeutic strategies. AMPD1 ATIC ITPA adenosine hypothesis genetic polymorphism purine metabolism schizophrenia treatment-resistant schizophrenia adenozinska hipoteza genetski polimorfizem presnova purinov shizofrenija na zdravljenje odporna shizofrenija true false true Angleški jezik Slovenski jezik Članek v reviji 2026-08-20 09:57:47 2026-08-20 09:57:57 2026-09-07 10:04:06 0000-00-00 00:00:00 2026 0 0 11 str. art. 1876365 Vol. 17 Jul. 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577.2:616.89 1663-9812 10.3389/fphar.2026.1876365 288022531 RAZ_Pjevac_Milica_2026.pdf RAZ_Pjevac_Milica_2026.pdf 1 9A4FAFB8B59C487CD464362E17EAB4DE d0dfea459d85d153a6d6f800972e5442e063b4ea9e402906d1bd45e782efaa36 d94f833c-9c6c-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=244720 https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1876365/full 1 7940080a-9c6c-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=244712 Medicinska fakulteta 0 0 0