Angiotensinogen Gene and Human Hypertension

NCT ID: NCT00063492

Last Updated: 2013-07-24

Basic Information

• Recruitment Status: COMPLETED
• Study Classification: OBSERVATIONAL
• Study Start Date: 2003-01-31
• Study Completion Date: 2007-12-31

Brief Summary

To determine the role of the angiotensinogen gene in human hypertension.

Detailed Description

BACKGROUND:

Essential hypertension affects at least 25 percent of American adults, and it is a primary risk factor for heart failure, stroke, and kidney disease. Many, but not all, studies have shown that variants of the angiotensinogen gene (AGT) affect the risk of hypertension, but association studies conducted to date have been compromised by genetic heterogeneity and by the inherent complexity of hypertension as a phenotype.

DESIGN NARRATIVE:

A comprehensive study of the angiotensinogen (AGT) gene will be conducted in data collected from several large groups of individuals. The investigators will sequence or genotype a 14.4 kb region including AGT in more than 1,600 individuals sampled from populations throughout the world. This will permit them to explore fully the extent of allelic heterogeneity, haplotype variation, and potential for population stratification in the AGT gene. Approximately 600 of these individuals are clinically uncharacterized and will represent a broad range of worldwide human variation. Another 500 subjects are members of 40 Utah pedigrees that are part of the Centre d'Etude du Polymorphisme Humain (CEPH) collection. These unique families have been heavily characterized genetically, and they are now being phenotyped for variables that include anthropometrics, blood chemistries, blood pressure measures, and plasma and urinary angiotensinogen. They will address the issue of genetic heterogeneity by testing associations between multi-SNP AGT haplotypes, angiotensinogen levels, and blood pressure. In addition, linkage disequilibrium patterns will be assessed to determine the density and nature of SNPs best suited for localizing a gene underlying a complex trait. They will address the issue of phenotypic heterogeneity in hypertension by performing extensive SNP typing on a set of 400 hypertensives and 100 normotensives collected by Dr. Gordon Williams. These clinically well-characterized subjects have been tested for their response to infused angiotensin-II under high and low sodium intake. This direct probe provides a hypertension endophenotype that is closer to the function of the AGT gene, yielding a more realistic and informative assessment of the relationship between AGT haplotype variation and hypertension risk. A phylogenetic analysis of AGT sequence variation in the worldwide sample will help to assess population stratification in association studies. In addition, this sample will allow testing the hypothesis that the ancestral T235 AGT allele provided a selective advantage in the sodium-poor environment of sub-Saharan Africa. The results of this analysis may help to explain why African-Americans have elevated rates of hypertension. In summary, the extensive analysis of AGT variation in more than 1,600 subjects will clarify the role of this gene in essential hypertension and will test specific hypotheses about the evolution of AGT.

Conditions

Cardiovascular Diseases; Heart Diseases; Hypertension

Eligibility Criteria

Inclusion Criteria

No eligibility criteria

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Utah

OTHER

Sponsor Role: lead

Principal Investigators

Lynn Jorde

Role:

University of Utah

References

Nakajima T, Wooding S, Satta Y, Jinnai N, Goto S, Hayasaka I, Saitou N, Guan-Jun J, Tokunaga K, Jorde LB, Emi M, Inoue I. Evidence for natural selection in the HAVCR1 gene: high degree of amino-acid variability in the mucin domain of human HAVCR1 protein. Genes Immun. 2005 Aug;6(5):398-406. doi: 10.1038/sj.gene.6364215.

Reference Type: BACKGROUND

PMID: 15889130 (View on PubMed)

Other Identifiers

R01HL070048

Identifier Type: NIH

Identifier Source: secondary_id

View Link

1215

Identifier Type: -

Identifier Source: org_study_id