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HEMODYNAMICS AND CARDIORENAL INTEGRATION

A haplotype of human angiotensinogen gene containing –217A increases blood pressure in transgenic mice compared with –217G

¹Department of Pathology, New York Medical College, Valhalla, New York; and ²Department of Microbiology and Immunology, Dartmouth Medical College, Lebanon, New Hampshire

Submitted 29 July 2008 ; accepted in final form 17 October 2008

The human angiotensinogen (hAGT) gene contains an A/G polymorphism at –217, and frequency of –217A allele is increased in African-American hypertensive patients. The hAGT gene has seven polymorphic sites in the 1.2-kb 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, the 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 hypoxanthine phosphoribosyltransferase locus. We show here that 1) hAGT mRNA level is increased in the liver by 60% and in the kidney by 40%; and 2) plasma AGT level is increased by 40%, and plasma angiotensin II level is increased by 50% in male double transgenic mice containing AA haplotype of the hAGT gene compared with the AG haplotype. In addition, systolic blood pressure is increased by 8 mmHg in transgenic mice containing the AA haplotype compared with 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.

polymorphism; hypertension; hypoxanthine phosphoribosyltransferase

This article has been cited by other articles:

				C. D. Sigmund 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. Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2008; 295(6): R1846 - R1848. [Full Text] [PDF]