Electrolyte Blood Press.  2013 Jun;11(1):24-28. 10.5049/EBP.2013.11.1.24.

Adrenergic Genetic Mechanisms in Hypertension and Hypertensive Kidney Disease

• Kang SW

• KMID: 2168397
• DOI: http://doi.org/10.5049/EBP.2013.11.1.24

Abstract

Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. In the tyrosine hyroxylase promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, 2 independent case-control studies (1,266 subjects with 53% women and 927 subjects with 24% women) replicated the effect of C-824T in the determination of blood pressure. Chromogranin A (CHGA) plays a fundamental role in the biogenesis of catecholamine secretory granules. Changes in the storage and release of CHGA in clinical and experimental hypertension prompted us to study whether genetic variation at the CHGA locus might contribute to alterations in autonomic function, and hence hypertension and its target organ consequences such as hypertensive kidney disease (nephrosclerosis). Systematic polymorphism discovery across the human CHGA locus revealed such regulatory regions as the proximal promoter and 3'-UTR. In chromaffin cell-transfected CHGA 3'-UTR and promoter/luciferase reporter plasmids, the functional consequences of the regulatory/non-coding allelic variants were documented. Variants in both the proximal promoter and the 3'-UTR displayed statistical associations with hypertension and hypertensive end stage renal disease. Therefore, I would like to review the common genetic variation in TH and CHGA as a cause of inter-individual variation in sympathetic activity, and ultimately blood pressure and hypertensive kidney disease.

Keyword

Blood pressure; Chromogranin A; Tyrosine hydroxylase; Hypertensive renal disease; Genomics

MeSH Terms

Blood Pressure
Case-Control Studies
Chromogranin A
Female
Genetic Variation
Genomics
Haplotypes
Humans
Hypertension
Kidney
Kidney Diseases
Kidney Failure, Chronic
Norepinephrine
Plasmids
Regulatory Sequences, Nucleic Acid
Secretory Vesicles
Tyrosine
Tyrosine 3-Monooxygenase
Organelle Biogenesis
Chromogranin A
Norepinephrine
Tyrosine
Tyrosine 3-Monooxygenase

Figure

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  Fig. 1 The catecholamine biosynthetic pathway.

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  Fig. 2 Intermediate phenotype.

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  Fig. 3 Influence of tyrosine hydroxylase promoter polymorphism (C-824T) on catecholamine excretion in twins.

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  Fig. 4 Influence of tyrosine hydroxylase promoter polymorphism (C-824T) on blood pressure response to stress in twins.

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  Fig. 5 Tyrosine hydroxylase promoter haplotype 2: Pleiotropy. Coordinate effects on both catecholamine exretion and stress blood pressure response in twins.

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  Fig. 6 Tyrosine hydroxylase: common SNP haplotype variation in the proximal promoter (C-824T/A-581G) predicts in vitro promoter strength as well as in vivo norepinephrine excretion in twins.

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