Angiotensinogen gene core promoter variants and non-modulating hypertension.
Non-modulation has been suggested as a possible intermediate phenotype defining a subgroup of genetic hypertension. The trait is characterized by an attenuated response of renal blood flow and/or aldosterone to angiotensin (Ang) II. We tested the hypothesis that functional polymorphisms of the core promoter of the angiotensinogen gene are associated with non-modulation. Fifty-six young, white, male, untreated hypertensive patients and 65 age-matched normotensive volunteers were genotyped for 3 known functional variants of the angiotensinogen core promoter. All subjects were infused with 2 doses (0.5 and 3 ng/kg per minute) of Ang II while they were on a high sodium diet (250 mmol/d). The blood pressure, renal plasma flow, and aldosterone responses to Ang II were not affected by the -6 G/A polymorphism. The -20 A/C variant had no significant effects on the blood pressure or renal hemodynamic response to Ang II. However, the aldosterone response to both doses of Ang II was significantly decreased in -20 C allele carriers compared with -20 AA homozygotes in a multivariate analysis. The -18 T allele was not detected in our population, and there was a linkage dysequilibrium between -20 C and -6 A: -20 C almost exclusively occurred on the -6 A allele. Haplotype analysis indicated that the -20 C/-6 A haplotype but not the -20 A/-6 A haplotype was associated with a decreased aldosterone response to Ang II. We conclude that the -20 C variant or the -20 C/-6 A haplotype of the angiotensinogen core promoter is associated with a blunted aldosterone response to Ang II and may thus contribute to the non-modulating phenotype.
Hilgers
K F
KF
Department of Medicine/Nephrology, University of Erlangen-Nürnberg, Nürnberg, Germany.
Delles
C
C
Veelken
R
R
Schmieder
R E
RE
D000328:Adult; D000450:Aldosterone / Q000097:blood; D000808:Angiotensinogen / Q000235:genetics*; D000809:Angiotensins / Q000494:pharmacology; D008040:Genetic Linkage / Q000235:genetics; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000178:diet therapy / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012982:Sodium, Dietary; D014158:Transcription, Genetic / Q000235:genetics
D000809:Angiotensins; D012982:Sodium, Dietary; D000808:Angiotensinogen; D000450:Aldosterone