The pharmacogenetics of Taiwanese psychiatric patients: The relationship between CYP1A2 gene -163A/C single nucleotide polymorphism and clozapine clearance, and the effect of alpha-2A Adrenergic receptor gene -1291C/G single nucleotide polymorphism on methylphenidate response

• Main Authors: Huang, Hui-Ching, 黃輝慶
• Other Authors: Liu, Chao-Zong
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/cx64zs

博士 === 慈濟大學 === 藥理暨毒理學碩士班/博士班 === 105 === Background: In clinical practice, great variability exists among individuals in response to drug therapy, and it is difficult to predict how effective or safe a medication will be for a particular patient. Pharmacogenetics is the study of how genetic differences affect variation in response to medication and its goals are to optimize drug therapy and limit drug toxicity based on an individual genetic profile. In pharmacogenetic studies antipsychotic drugs are of particular interest as they are associated with a large interindividual variability in terms of response and side effects, and frequently need to be discontinued, requiring switches to other antipsychotics. Here we carried out two pharmacogenetic studies designed to explore whether a single nucleotide polymorphism (SNP) at the drug metabolizing cytochrome P450 1A2 (CYP1A2), -163 A/C, correlates with the plasma level of clozapine (CLZ) and whether a SNP of at the adrenergic receptor 2A (ADRA2A) gene encoding drug target, -1291 C/G (classically known as CYP1A2*1F), correlates with response to methylphenidate (MPH) treatment in Taiwanese psychiatric patients. Methods: In the first study, 143 hospitalized schizophrenic patients who had taken CLZ for at least 14 days were enrolled. Whole blood was collected in the morning before drug administration. Plasma level of CLZ was determined by using LC-MS-MS. DNA sequencing and RFLP were used to analyze the SNP at CYP1A2 gene. The effect of smoking on the CLZ level was examined by multiple linear regression analysis and the effect of smoking on CLZ level in association with the -163A/C SNP was analyzed by general linear model with Bonferroni correction. In the second study, 59 children from a child psychiatric clinic in Hualien Taiwan consecutively diagnosed as having attention-deficit/ hyperactivity disorder (ADHD) were genotyped for the ADRA2A gene -1291 C > G SNP. A clinical response to treatment with MPH was defined as an improvement of more than 25% in the SNAP IV rating scale. Subjects who had 50% or greater improvement after treatment were defined to have better response whereas moderate response was defined as having improvement between 25% and 50%. Whole blood was collected six hours after drug administration. Plasma level of MPH was determined by using LC-MS-MS. The SNP at ADRA2A gene was analyzed by DNA sequencing. Binary logistic regression analysis was employed to examine the relationship between the SNP and MPH treatment response. Results: In the first study, the schizophrenic patients with smoking habit exhibited a significant lower plasma CLZ level than those without smoking habit (p=0.02), and the effect of smoking on the plasma level of clozapine was significant among patients carrying homozygous -163A allele (p=0.02). Also, in non-smokers, those who carry the -163A allele tended to have higher plasma CLZ levels in comparison with CC homozygotes . This tendency was not revealed in patients with smoking habit. Results of the second study indicated that 74.6% subjects (44/59) exhibited more than 25% improvement following MPH treatment. The effect of MPH was not associated with the ADRA2A gene -1291C/G SNP, but responders with GG homozygotes displayed a higher rate of better response following MPH treatment and the difference of better response rate between GG homozygotes and CC homozygotes reached a statistical significance (OR=32.14, 95% CI=1.64 – 627.80, p=0.02). Conclusions: In the first study, I demonstrated that cigarette smoking has a significant impact on the plasma CLZ level in Taiwanese schizophrenic patients and the effect of smoking on the plasma level of clozapine is associated with CYP1A2 gene -163A/C SNP. Cigarette smoking may increase the clearance of CLZ in AA homozygotes. Smokers with the A-allele might require a higher CLZ maintenance dose for an adequate clinical response. On the other hand, non-smokers with CC genotype would be at risk of treatment resistance due to increased CLZ clearance. Data from the second study demonstrated that ADRA2A gene -1291C/G SNP is associated with the efficacy of MPH for the treatment of ADHD in Taiwanese children and adolescents. The carriers of homozygous G allele exhibited a better response under MPH treatment. Overall, it merits a large population-based prospective study to validate these findings and more evidences needed before putting this idea into clinical practice.