The human angiotensinogen (hAGT) gene contains an A/G polymorphism at -217 and frequency of -217A allele is increased in African-American hypertensive patients. hAGT gene has seven polymorphic sites in 1.2Kb region of its promoter and variant -217A almost always occurs with -532T, -793A, and -1074T whereas variant -217G almost always occurs with -532C, -793G, and -1074G. Since allele -6A is the predominant allele in African-Americans, AGT gene can be subdivided into two main haplotypes -6A:-217A (AA) and -6A:-217G (AG). To understand the role of these haplotypes on hAGT gene expression and on blood pressure regulation in an in vivo situation, we have generated double transgenic mice containing human renin gene and either AA or AG haplotype of the hAGT gene using knock-in strategy at the HPRT locus. We show here that: (a) hAGT mRNA level is increased in the liver by 60% and in the kidney by 40%, (b) plasma AGT level is increased by about 40% and plasma angiotensin-II level is increased by about 50% in male double transgenic mice containing AA haplotype of the hAGT gene as compared to the AG haplotype. In addition systolic blood pressure is increased by 8 mmHg in transgenic mice containing AA haplotype as compared to the AG haplotype. This is the first report to show the effect of polymorphisms in the promoter of a human gene on its transcription in an in vivo situation that ultimately leads to an increase in blood pressure.