Hartz Philip, Fehlmann Tobias, Wagenpfeil Gudrun, Unger Marcus Michael, Bernhardt Rita
Institut für Biochemie, Fachbereich Biologie, Universität des Saarlandes, Naturwissenschaftlich-Technische Fakultät, Saarbrücken, Germany.
Institut für Klinische Bioinformatik, Universität des Saarlandes, Saarbrücken, Germany.
Front Pharmacol. 2023 Jan 19;13:1094265. doi: 10.3389/fphar.2022.1094265. eCollection 2022.
Genetic and environmental factors lead to the manifestation of Parkinson's disease (PD) but related mechanisms are only rudimentarily understood. Cytochromes P450 (P450s) are involved in the biotransformation of toxic compounds and in many physiological processes and thus predestinated to be involved in PD. However, so far only SNPs (single nucleotide polymorphisms) in and have been associated with the susceptibility of PD. Our aim was to evaluate the role of all 57 human P450s and their redox partners for the etiology and pathophysiology of PD and to identify novel potential players which may lead to the identification of new biomarkers and to a causative treatment of PD. The PPMI (Parkinson's Progression Markers Initiative) database was used to extract the gene sequences of all 57 P450s and their three redox partners to analyze the association of SNPs with the occurrence of PD. Applying statistical analyses of the data, corresponding odds ratios (OR) and confidence intervals (CI) were calculated. We identified SNPs significantly over-represented in patients with a genetic predisposition for PD (GPD patients) or in idiopathic PD (IPD patients) compared to HC (healthy controls). Xenobiotic-metabolizing P450s show a significant accumulation of SNPs in PD patients compared with HC supporting the role of toxic compounds in the pathogenesis of PD. Moreover, SNPs with high OR values (>5) in P450s catalyzing the degradation of cholesterol (CYP46A1, CY7B1, CYP39A1) indicate a prominent role of cholesterol metabolism in the brain for PD risk. Finally, P450s participating in the metabolism of eicosanoids show a strong over-representation of SNPs in PD patients underlining the effect of inflammation on the pathogenesis of PD. Also, the redox partners of P450 show SNPs with OR > 5 in PD patients. Taken together, we demonstrate that SNPs in 26 out of 57 P450s are at least 5-fold over-represented in PD patients suggesting these P450s as new potential players in the pathogenesis of PD. For the first time exceptionally high OR values (up to 12.9) were found. This will lead to deeper insight into the origin and development of PD and may be applied to develop novel strategies for a causative treatment of this disease.
遗传和环境因素导致帕金森病（PD）的表现，但相关机制仅得到初步了解。细胞色素P450（P450s）参与有毒化合物的生物转化以及许多生理过程，因此注定与帕金森病有关。然而，到目前为止，只有CYP1A1和CYP2D6中的单核苷酸多态性（SNPs）与帕金森病的易感性相关。我们的目的是评估所有57种人类P450及其氧化还原伴侣在帕金森病的病因学和病理生理学中的作用，并确定可能导致识别新生物标志物和对帕金森病进行病因治疗的新潜在因素。使用帕金森病进展标志物倡议（PPMI）数据库提取所有57种P450及其三种氧化还原伴侣的基因序列，以分析SNPs与帕金森病发生的关联。对数据进行统计分析，计算相应的比值比（OR）和置信区间（CI）。我们发现，与健康对照（HC）相比，在具有帕金森病遗传易感性的患者（GPD患者）或特发性帕金森病（IPD患者）中，SNPs显著过度存在。与HC相比，参与异源生物代谢的P450s在帕金森病患者中显示出SNPs的显著积累，这支持了有毒化合物在帕金森病发病机制中的作用。此外，催化胆固醇降解的P450s（CYP46A1、CY7B1、CYP39A1）中具有高OR值（>5）的SNPs表明胆固醇代谢在大脑中对帕金森病风险起着重要作用。最后，参与类花生酸代谢的P450s在帕金森病患者中显示出SNPs的强烈过度存在，突出了炎症对帕金森病发病机制的影响。此外，P450的氧化还原伴侣在帕金森病患者中也显示出OR>5的SNPs。综上所述，我们证明57种P450中有26种的SNPs在帕金森病患者中至少过度存在5倍，表明这些P450是帕金森病发病机制中的新潜在因素。首次发现了异常高的OR值（高达12.9）。这将有助于更深入地了解帕金森病的起源和发展，并可能应用于开发针对这种疾病的病因治疗新策略。
