Klemm Marco, Eidens Moritz, Lorenz Marion, Prause Stefan, Weise Alexander, Dahmen Norbert, Forst Thomas, Pfützner Andreas
PharmGenomics GmbH, Mainz, Germany.
Clin Lab. 2010;56(9-10):473-80.
The cytochrome P450 1A2 (CYP1A2) gene encodes one of the most important enzymes of the Phase I drug metabolism, which is involved in the metabolism of many lipophilic xenobiotics, such as haloperidol, theophylline, phenacetine, and others. The recently discovered single nucleotide polymorphisms CYP1A21C (-3860G-->A) in the 5' flanking region of the gene and CYP1A21F (-163C-->A) in intron 1 seem to interfere with the expression rate or catalytic function of the enzyme. Polymorphism carriers may either have a risk of reduced drug degradation and side effects, or may present with an increased induction of enzymatic activity resulting in clinical non-response to the prescribed therapy. We investigated two populations, a mental disease group and a healthy control group, to identify whether these two genetic variants are correlated with the general development of a mental disorder and if they could potentially be used as predictive markers for manifestation of the same.
Using specifically designed primers, we established a high-throughput multiplex screening realtime PCR method for the two polymorphisms on the CYP1A2 gene with the Roche LightCycler instrument.
We analysed the two cohorts to identify whether one of the two described genetic variants may be associated with the manifestation of a mental disorder in general. For the CYP1A21C variant, we identified an allele frequency of 1.7% for both cohorts. For the CYP1A1F polymorphism, we found an allele frequency of 74.5% for the mental disease group and 68.6% for the healthy control group.
This new diagnostic method of multiplex detection may be helpful to routinely identify carriers of CYP1A2 variants and to improve the therapeutic effectiveness by selection of the most appropriate therapeutic regimen. As a result of this pilot study, there appeared to be no significant correlation between the existence of one of the investigated genetic variants and the development of a mental disorder.
细胞色素P450 1A2（CYP1A2）基因编码参与I期药物代谢的最重要的酶之一，该酶参与许多亲脂性外源性物质的代谢，如氟哌啶醇、茶碱、非那西丁等。最近在该基因5'侧翼区域发现的单核苷酸多态性CYP1A21C（-3860G→A）和内含子1中的CYP1A21F（-163C→A）似乎会干扰该酶的表达率或催化功能。多态性携带者可能有药物降解减少和副作用的风险，或者可能表现出酶活性诱导增加，导致对规定治疗无临床反应。我们调查了两个群体，一个精神疾病组和一个健康对照组，以确定这两种基因变异是否与精神障碍的总体发展相关，以及它们是否有可能作为精神障碍表现的预测标志物。
使用专门设计的引物，我们用罗氏LightCycler仪器建立了一种用于CYP1A2基因上这两种多态性的高通量多重筛选实时PCR方法。
我们分析了这两个队列，以确定所描述的两种基因变异中的一种是否可能与精神障碍的表现总体相关。对于CYP1A21C变异，我们在两个队列中均确定其等位基因频率为1.7%。对于CYP1A1F多态性，我们发现精神疾病组的等位基因频率为74.5%，健康对照组为68.6%。
这种新的多重检测诊断方法可能有助于常规识别CYP1A2变异的携带者，并通过选择最合适的治疗方案提高治疗效果。作为这项初步研究的结果，所研究的基因变异之一的存在与精神障碍的发展之间似乎没有显著相关性。
