A growing chain of evidence linking genetic variation in angiotensinogen with essential hypertension: focus on "a haplotype of human angiotensinogen gene containing -217A increases blood pressure in transgenic mice compared with -217G," by Jain et al.
A growing chain of evidence linking genetic variation in angiotensinogen with essential hypertension: focus on "a haplotype of human angiotensinogen gene containing -217A increases blood pressure in transgenic mice compared with -217G," by Jain et al.
Project description:Hypertension is a serious risk factor for cardiovascular disease, and the angiotensinogen (AGT) gene locus is associated with human essential hypertension. The human AGT (hAGT) gene has an A/G polymorphism at -6, and the -6A allele is associated with increased blood pressure. However, transgenic mice containing 1.2 kb of the promoter with -6A of the hAGT gene show neither increased plasma AGT level nor increased blood pressure compared with -6G. We have found that the hAGT gene has three additional SNPs (A/G at -1670, C/G at -1562, and T/G at -1561). Variants -1670A, -1562C, and -1561T almost always occur with -6A, and variants -1670G, -1562G, and -1561G almost always occur with -6G. Therefore, the hAGT gene may be subdivided into either -6A or -6G haplotypes. We show that these polymorphisms affect the binding of HNF-1α and glucocorticoid receptor to the promoter, and a reporter construct containing a 1.8-kb hAGT gene promoter with -6A haplotype has 4-fold increased glucocorticoid-induced promoter activity as compared with -6G haplotype. In order to understand the physiological significance of these haplotypes in an in vivo situation, we have generated double transgenic mice containing either the -6A or -6G haplotype of the hAGT gene and the human renin gene. Our ChIP assay shows that HNF-1α and glucocorticoid receptor have stronger affinity for the chromatin obtained from the liver of transgenic mice containing -6A haplotype. Our studies also show that transgenic mice containing -6A haplotype have increased plasma AGT level and increased blood pressure as compared with -6G haplotype. Our studies explain the molecular mechanism involved in association of the -6A allele of the hAGT gene with hypertension.
Project description:In patients with primary breast cancer, neoadjuvant chemotherapy with doxorubicin plus pemetrexed followed by docetaxel (AP-D) is associated with a pathologic complete response (pCR) rate of 16.5%, and doxorubicin plus cyclophosphamide followed by docetaxel (AC-D) is associated with a pCR rate of 20.2%. Our primary objective was to identify single predictive genetic markers for achievement of pCR following either AP-D or AC-D treatment. Our main secondary objective was to detect treatment-group specific, pCR-predictive gene signatures.
Project description:Comparative genomic hybridization experiments comparing DNA from experimentally evolved yeast strains to DNA from a euploid control.