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<p>Alterations in tryptophan (Trp) metabolism are of potential significance for the pathophysiology of Schizophrenia (SCZ). However, the genetics of kynurenine pathway (KP) enzymes remains poorly investigated. The aim of this study was (i) to examine the rs34820341, rs10109853, rs1480544, and rs2275163 polymorphisms in the <i>IDO1</i>, <i>IDO2</i>, <i>KAT</i> II, and <i>KMO</i> genes, respectively, in a Tunisian population comprising 247 SCZ patients and 265 controls; (ii) to assess the relationship between the IDO1 inducer (IFNγ) and inhibitor (IL-10), together with the neuroactive quinolinic acid (QA) and kynurenic acid (KA), in plasma samples from relapsed patients (<i>n</i> = 23) at admission and after antipsychotic treatment compared with healthy subjects (<i>n</i> = 28); and (iii) to quantify <i>IDO1</i> and <i>IDO2</i> mRNA expression in PBMCs from these groups. Our results revealed that the rs34820341 V1 allele and V1/V2–V1/V1 genotypes exhibit a significant risk for male predisposition to SCZ (P<sub>A</sub>=0.01; P<sub>A</sub>=0.006, respectively), more specifically to undifferenciated subtype (P<sub>A</sub>=0.02; P<sub>A</sub>=0.013, respectively). Diplotypic examination of rs34820341_rs10109853 in <i>IDO1</i> and <i>IDO2</i> genes unveils that V2-T combination confers protection from paranoid SCZ (OR = 0.21, P<sub>A</sub>=0.0024) in males. Relapsed patients, who initially display high levels of pro-inflammatory IFNγ (<i>p</i> = 0.005) and neurotoxic QA (<i>P</i> = 0.007) compared to the control group, maintain increased IFNγ levels (<i>P</i> = 0.004) and show a tendency to QA reduction (<i>P</i> = 0.08) under antipsychotic treatment. Only <i>IDO1</i> mRNA expression was significantly upregulated in both admitted and discharged SCZ patients (<i>P</i> &lt; 0.0001). Our study supports a role of the <i>IDO1</i> gene in SCZ susceptibility, but further individual and diplotypic genetic analyses are necessary to further explore <i>IDO1/2</i> genes.</p>

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Sex-specific association of IDO1 gene with schizophrenia and imbalanced levels of cytokines and neuroactive kynurenine metabolites in relapsed patients

  • 期刊论文

  • 发表日期：

    2025年12月27日

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  • Amira Ben Afia,
  • Karina S. MacDowell,
  • David Martín-Hernández,
  • Farid Zaafrane,
  • Lotfi Gaha,
  • Juan C. Leza,
  • Besma Bel Hadj Jrad

摘要

Alterations in tryptophan (Trp) metabolism are of potential significance for the pathophysiology of Schizophrenia (SCZ). However, the genetics of kynurenine pathway (KP) enzymes remains poorly investigated. The aim of this study was (i) to examine the rs34820341, rs10109853, rs1480544, and rs2275163 polymorphisms in the IDO1, IDO2, KAT II, and KMO genes, respectively, in a Tunisian population comprising 247 SCZ patients and 265 controls; (ii) to assess the relationship between the IDO1 inducer (IFNγ) and inhibitor (IL-10), together with the neuroactive quinolinic acid (QA) and kynurenic acid (KA), in plasma samples from relapsed patients (n = 23) at admission and after antipsychotic treatment compared with healthy subjects (n = 28); and (iii) to quantify IDO1 and IDO2 mRNA expression in PBMCs from these groups. Our results revealed that the rs34820341 V1 allele and V1/V2–V1/V1 genotypes exhibit a significant risk for male predisposition to SCZ (PA=0.01; PA=0.006, respectively), more specifically to undifferenciated subtype (PA=0.02; PA=0.013, respectively). Diplotypic examination of rs34820341_rs10109853 in IDO1 and IDO2 genes unveils that V2-T combination confers protection from paranoid SCZ (OR = 0.21, PA=0.0024) in males. Relapsed patients, who initially display high levels of pro-inflammatory IFNγ (p = 0.005) and neurotoxic QA (P = 0.007) compared to the control group, maintain increased IFNγ levels (P = 0.004) and show a tendency to QA reduction (P = 0.08) under antipsychotic treatment. Only IDO1 mRNA expression was significantly upregulated in both admitted and discharged SCZ patients (P < 0.0001). Our study supports a role of the IDO1 gene in SCZ susceptibility, but further individual and diplotypic genetic analyses are necessary to further explore IDO1/2 genes.