Studies On Candidate Genes Of Essential Hypertension And Antihypertensive Pharmacogenomics

Essential hypertension (EH) is a polygenetic disease that occurs as a consequence of complex interactions of multiple genetic polymorphisms and environmental factors. High blood pressure may increase the risk factor of cardiovascular and cerebrovascular diseases, which have affected on public health. The focus of hypertensive prevention and cure is the investigation of heritable susceptibility and pharmacogenomics of blood pressure response to antihypertensive treatment, but the actual molecular mechanisms underlying EH remain obscure to date. With the completion of the Human Genome Project and the birth of gene chip genotyping technology, there has been a theoretical and technical foundation for studying candidate genes of EH and antihypertensive pharmacogenomics. To investigate the genetic background of EH, a community-based case-control study was performed in Jiangsu Province. The 16 SNP sites were detected in 11 genes, including RAAS, sympathetic nervous system, the protein of impact on endothelial function, and the G protein of mediating signal transduction. The proteins encoded by these genes may have a relationship with blood pressure (BP ) regulatory mechanisms by different pathways. After the gene chip technology was used to genotype the SNPs, the genotypes, alleles and hyplotypes were analysed to explore the genetic trait of these candidate genes in the study population. We attempted to highlight the most important existing genetic variations of candidate genes and their potential roles in the development of EH. To research the correlation of candidate genes polymorphisms with antihypertensive effects, some EH patients were randomly chosen to undergo monotherapy with Hydrochlorothiazide or Betaloc for four weeks, respectively. The studies we have conducted will be helpful to screen the EH patients in the earlier period and timely prevent EH. Furthermore, some principles of pharmacogenomics may provide basis for designing optimal individualized drug treatment for hypertensive patients.Part 1 Studies on Candidate Genes of Essential HypertensionA case-control study was carried out, including 190 patients and 94 normotensive individuals. During the study, We explored 16 SNP sites in 11 candidate genes of EH, aiming at identifying those variants and haplotypes asscociated with the risk of EH. Our results suggested that the A(-6 ) G G allele and T174M T allele of AGT gene, the I/D DD genotype of ACE gene, the G894T T allele of eNOS gene and the A1166C A allele of AT1R gene might increase the risk of EH, respectively. While haplotype( -6 )A, 174C, (-217 )G, (-20 )A of AGT gene might decrease the risk of EH.Part 2 Studies on Antihypertensive PharmacogenomicsTo study the correlation of candidate genes polymorphisms with the antihypertensive effects of Hydrochlorthiazide and Betaloc in EH patients, 108 EH patients from Part 1 were randomly divided into two groups. Every patient in one group received Hydrochlorthiazide (12.5mg, once daily) for four weeks, while each one in the other group received Betaloc (25mg, twice daily) the same for four weeks. Our results suggested that the polymorphisms of CYP11B2 T (-344 ) C and AGT G (-6 ) A might be associated with antihypertensive effects of Hydrochlorthiazide, especially in the patients with the CC genotype and G allele. And the patients with the combination of CYP11B2 CC genotype and ADD1 T allele might have better BP response to Hydrochlorthiazide than those any other genotypic combinations of the two genes. Moreover, the polymorphisms of GNB3 C825T andβ2 - AR A46G might be associated with antihypertensive effects of Betaloc, especially in the patients with the T and A allele. Meanwhile, we also found that the patients with CC genotype of CYP11B2 gene might have better blood pressure response to Hydrochlorthiazide than to Betaloc, but the patients with CT or TT genotype might have contrary results.