The Association between the Genetic Polymorphisms and the Susceptibility of Parkinson''s Disease, and the Effects of Catechol-O-Methyltransferase Genotypes on the Clinical Responses of Tolcapone

• Main Authors: Shiang-Lin Lu, 呂相琳
• Other Authors: Yunn-Fang Ho
• Format: Others
• Language: zh-TW
• Published: 1999
• Online Access: http://ndltd.ncl.edu.tw/handle/00760092469679482772

碩士 === 國立臺灣大學 === 藥學研究所 === 87 === Parkinson''s disease is a common neurological disorder among the elderly, and its clinical manifestation includes tremor, akinesia and rigidity. Although the pathogenesis of this disease is still unknown, it was thought to be the genetic or environmental factors. In view of genetic aspect, evidence had often imply to the cytochrome P450 family and the enzymes by which dopamine is metabolized. Hypothesis that the enzymes might play an important role in the susceptibility of Parkinson''s disease such as: COMT, MAO-B, CYP2E1 and CYP1A1.Levodopa, the precursor of dopamine, has been the most effective drug in the therapy of Parkinson''s disease for many years. Despite its effectiveness, it can not prevent the progression of the disease, and almost half of the patients develop on/off phenomenon after 5 years usage. Combining COMT inhibitor with levodopa can prolong the half-life of levodopa and ameliorate the fluctuation response in Parkinson''s disease. It has been reported that after they use levodopa, the COMTH patients produce more severe dyskinesia symptom than the COMTL patients, and the duration of drug effect is shorter, too. Therefore, maybe a greater effect of COMT inhibitor can be expected in the COMTH patients than the COMTL patients.We conducted a case-control study with all the cases diagnosed Parkinson''s disease by neurological doctors. The controls are carefully matched with the cases in age, sex and geographical area. We use a buccal brush to collect the buccal mucosa swabs of each sample. Then we complete the genotyping of COMT, MAO-B, CYP2E1 and CYP1A1 polymorphism by using restriction fragment length polymorphism analysis and compare the distribution frequency between the cases and the controls. Furthermore, we divide the 20 patients who participate in the tolcapone clinical trial into two groups according to their genotype and compare if there''s any difference between their percentage change in % OFF time and UPDRS scoring.In our results, we can see that there is significant difference in the distribution of MAO-B genotypes between the cases and the controls in males (p=0.016) but not females (p=0.59). The odds ratio of G allele to A allele is 2.14 in men, which is statistically significant. There are no differences in the other three genetic polymorphisms, but a synergistic effect can be seen in the COMT and MAO-B polymorphisms. In the evaluation of the effect of COMT polymorphism on tolcapone, we found that the percent change in % OFF time (p=0.048) and UPDRS IV-A (p=0.04) score is significantly higher in the wild type patients. Because of the small sample size in this study, we can not see significant differences in other secondary parameters.We can see that the MAO-B intron 13 polymorphism may be a susceptibility factor in the pathogenesis of Parkinson’s disease, especially in the G allele of men. Although the impact of COMT polymorphism on Parkinson’s disease is not as significant as that of MAO-B, their synergistic effect could not be ignored. In view of COMTH patients shows more improvement than the COMTL patients after they used tolcapone, we could suggest that we can use a lower dose of tolcapone than the Caucasians since the frequency of COMTH is much more common in our population.