Studies Of Risperidone Pharmacogenomics In Schizophrenia And Genetics In Hypertension

Schizophrenia (MIM 181500) is a complex disorder affecting ~1% of the population worldwide. The disorder is characterized by psychotic symptoms and by cognitive, affective, and psychosocial impairment. Risperidone is an effective first-line atypical antipsychotic agent. In clinical therapy, a large proportion of patients will not respons after the treatment. Studies show that genetic factors play a very important role in the process.In the first part of the thesis, we used Chinese schizophrenia patients with 8 weeks risperidone treatment as our subjects. We assessed clinical syndrome by using PANSS and BPRS. The relationship between functional polymorphisms of CYP2D6, HTT, HT1A gene and risperidone therapy efficiency, plasma risperidone metabolic ratio was evaluated. We found that the C188T polymorphism of CYP2D6 affected plasma risperidone ratio; there is a relationship between two polymorphisms of HTT and change of BPRS scores; -1019 C/G polymorphism of HT1A determine the improvement of negative symptom of schizophrenia.Hypertension is a complex disorder, affecting 20-30% of the population. There are evidences that autonomic activities are related to blood pressure. To our knowledge, the development of hypertension is the result of interaction between many genes, such as genes in rennin-angiotensin-aldosterone system, catecholamine/epinephrine sytem under the pressure of environmental factors. Recent studies showed that NPY plays an important role in etiology of hypertension.In the second part of the thesis, we systermatically studied the Singal Nucleotide Polymorphisms of NPY1R. Two common SNPs were genotyped in the well-phenotyped twins samples and blood pressure extreme samples. We found the 3'-UTR polymorphism was associated with various kind of autonomic activities. In addition, promoter and 3'-UTR polymorphism were strongly associated with blood pressure. Luciferase experiments showed that the two polymorphisms were functional and both of them affected the luciferase expression. Bioinformatics prediction showed that the 3'-UTR polymorphism is located in the microRNA hsa-miR-511 binding site. Different allele of the SNP will result in the different minimum folding energy, which may affect the NPY1R expression and finally affect the blood pressure.