Tamimou Rabah, Montout Christine, Mura Thibault, Conejero Ismael, Evrard Alexandre, Courtet Philippe, Bonilla-Escribano Pablo, Riaza Carlos, Vaquero-Lorenzo Concepción, Baca-Garcia Enrique, Jollant Fabrice, Lumbroso Serge, Mouzat Kevin, Lopez-Castroman Jorge
Department of Psychiatry, Nîmes University Hospital, Nîmes, France.
IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France.
Brain Behav Immun Health. 2024 Nov 12;42:100903. doi: 10.1016/j.bbih.2024.100903. eCollection 2024 Dec.
Suicidal behavior has been associated with dysfunctions in the kynurenine pathway, including alterations in the levels of neuroprotective and neurotoxic metabolites. Changes in the catalytic activity of enzymes within the pathway may contribute significantly. Variations in the genes encoding enzymes within the pathway can significantly affect their catalytic activity, playing a crucial role in the process. To explore this possibility, we hypothesized that these genetic variations would occur more frequently in patients with a history of suicidal behavior compared to non-suicidal individuals. Thus, we investigated the relationship between a history of suicide attempts and five single nucleotide polymorphisms (SNPs) within genes involved in the kynurenine pathway: (rs7820268), (rs10109853), (rs1053230), (rs10988134), and (rs2121337). Our sample comprised 849 subjects: 325 individuals who had attempted suicide in their lifetime (SAs), 99 individuals with a history of major depression disorder but no previous suicide attempts (non-SAs), and 425 non-psychiatric controls (CTRL). We performed SNP association analyses using codominant, dominant, and recessive models. Adjustment for sex and multiple comparisons was applied. After adjustment, the analysis revealed that SAs showed a significantly higher frequency of T alleles and TT genotypes of the rs1053230 SNP compared to CTRL across nearly all models. Furthermore, in the recessive model, non-SAs displayed a higher prevalence of the TT genotype of the rs10109853 SNP compared to CTRL. The rs1053230 and rs10109853 SNPs could play a role in the previously observed metabolic dysregulation among SAs and non-SAs, respectively. To validate our findings, it is crucial to conduct functional analyses to investigate the impact of rs10109853 and rs1053230 SNPs on the expression and/or catalytic activity of the corresponding enzymes.
自杀行为与犬尿氨酸途径功能障碍有关，包括神经保护和神经毒性代谢物水平的改变。该途径中酶的催化活性变化可能起重要作用。该途径中编码酶的基因变异可显著影响其催化活性，在这一过程中起关键作用。为探究这种可能性，我们假设与非自杀个体相比，有自杀行为史的患者中这些基因变异会更频繁出现。因此，我们研究了自杀未遂史与犬尿氨酸途径相关基因中的五个单核苷酸多态性（SNP）之间的关系：（rs7820268）、（rs10109853）、（rs1053230）、（rs10988134）和（rs2121337）。我们的样本包括849名受试者：325名曾在一生中尝试过自杀的个体（自杀未遂者）、99名有重度抑郁症病史但以前没有自杀未遂的个体（非自杀未遂者）和425名非精神科对照者（对照组）。我们使用共显性、显性和隐性模型进行SNP关联分析。对性别和多重比较进行了校正。校正后，分析显示在几乎所有模型中，与对照组相比，自杀未遂者中rs1053230 SNP的T等位基因和TT基因型频率显著更高。此外，在隐性模型中，与对照组相比，非自杀未遂者中rs10109853 SNP的TT基因型患病率更高。rs1053230和rs10109853 SNP可能分别在先前观察到的自杀未遂者和非自杀未遂者的代谢失调中起作用。为验证我们的发现，进行功能分析以研究rs10109853和rs1053230 SNP对相应酶的表达和/或催化活性的影响至关重要。
