(Hypertension. 1998;32:402-403.)
© 1998 American Heart Association, Inc.
Editorial Commentary: Angiotensinogen Genotype and Blood Pressure Responses to Reduced Dietary NaCl and to Weight Loss
Theodore A. Kotchen
From the Department of Medicine, Medical College of Wisconsin
(Milwaukee).
Correspondence to Theodore A. Kotchen, MD, Department of Medicine, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226.
Key Words: angiotensinogen • blood pressure • genetics • clinical trials • Editorial
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Introduction
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With the human genome project nearing
completion and with the increasing availability of genotyping
technology, there is considerable interest in identifying genes that
contribute to hypertension and to physiological
determinants of hypertension. In a number of relatively rare
hypertensive disorders, specific genetic polymorphisms resulting in
elevated arterial pressure have recently been described,
eg, glucocorticoid-remediable primary aldosteronism, Liddle's
syndrome, and the syndrome of apparent mineralocorticoid
excess.1 In several but not all of these
disorders, hypertension is the consequence of alterations of either
adrenal steroid metabolism or direct renal tubular function
resulting in antinatriuresis. Conversely, specific polymorphisms
have been identified that result in alterations of renal tubular
function that promote natriuresis and consequently relatively low blood
pressure levels.
What relevance, if any, these or similar polymorphisms may have to
blood pressure regulation or hypertension in the general population
remains to be determined. Despite evidence for heritability, essential
hypertension is a complex trait that does not exhibit classic mendelian
modes of inheritance attributable to a single gene
locus.2 Multiple genetic loci may be involved in
blood pressure regulation, and hypertension may be related to the
interaction of susceptible genes with environmental stressors, such as
dietary sodium chloride (NaCl) consumption.
Trials of Hypertension Prevention (TOHP) is a longitudinal study
designed to evaluate the efficacy of reduction of dietary NaCl and of
weight loss on blood pressure in a cohort of moderately overweight
adults with diastolic blood pressures of 83 to 89
mm Hg.3 In this issue of
Hypertension, Hunt et al4 report that
different polymorphisms of the angiotensinogen gene are
associated with different levels of blood pressure in white subjects
participating in the trial. Furthermore, over the 36 months of study,
in response to both a reduced NaCl intake and weight loss, reduction of
diastolic blood pressure was greater and incidence of
hypertension was less in persons with the AA
angiotensinogen genotype compared with those with
the GG genotype. Blood pressure responses in persons with the
AG genotype were intermediate.
This study is important for several reasons. To have 3-year follow-up
data on 1509 subjects who have been randomized to a successful NaCl
and/or weight reduction intervention is a remarkable achievement. The
results highlight the limited contribution of a single polymorphism
of the angiotensinogen gene to blood pressure level and to
blood pressure responses to NaCl reduction and weight loss. Although
different blood pressure responses to NaCl reduction and weight loss
were observed by angiotensinogen genotype at 36
months, there were no differences at 6 or 18 months. Furthermore,
although angiotensinogen genotype was associated
with blood pressure responses to NaCl reduction alone and to weight
loss alone, it was not associated with blood pressure responses to the
combined NaCl reduction–weight loss intervention. The results would be
more credible if they had been consistent over time and if an
effect of angiotensinogen genotype had also been
observed in the combined intervention group.
Individuals with the AA genotype are homozygous for the T235
allele of the M235T polymorphism of angiotensinogen
(substitution of threonine for methionine at codon 235). In other
populations, linkage of this allele with essential hypertension has
not been consistently observed, reflecting either genetic
diversity among populations, the limited contribution of this locus to
hypertension, and/or methodological problems with several of the
studies.5 6 This is in stark contrast to the
monogenic hypertensive disorders in which a single mutation has a
profound effect on blood pressure. Cross-breeding experiments in the
rat (F2 progeny from a cross between normotensive
Brown Norway rats and spontaneously hypertensive rats) document that
each of a number of putative hypertensive alleles contribute to
blood pressure and that the height of the blood pressure is dependent
on the number of such alleles.7 Similarly, a
number of susceptibility genes may contribute to essential hypertension
and, as documented for the angiotensinogen gene, any single
polymorphism by itself may have a relatively small impact on blood
pressure level.
Within a population, there is considerable variability of blood
pressure responsiveness to NaCl intake, and salt sensitivity of blood
pressure should be considered a quantitative rather than a qualitative
trait.8 Heritability of salt sensitivity and salt
resistance of blood pressure is most convincingly documented in animal
models. Family studies, including twin studies, suggest that there is a
heritable contribution to salt sensitivity of blood pressure in humans,
and there is limited evidence for heritability of NaCl excretion and
levels of hormones that regulate NaCl
excretion.9 10 The study of Hunt et al suggests
that angiotensinogen genotype has, at best, a
modest influence on the blood pressure responses to NaCl reduction and
to weight loss. It is likely that additional genetic markers of salt
sensitivity will be identified, and similar to blood pressure level
itself, in any individual the magnitude of the effect of dietary NaCl
on blood pressure will reflect the culmination of a variable number
of genetic polymorphisms.
Hunt et al speculate that higher blood pressure levels and greater
blood pressure responses to reduced NaCl intake and to weight loss in
persons with the AA genotype are related to increased
angiotensinogen concentrations and failure to reduce plasma
angiotensin II concentrations in response to a high NaCl
intake. However, no measurements of angiotensinogen or
other components of the
renin-angiotensin-aldosterone system are
provided, and salt sensitivity of blood pressure is generally
associated with low rather than with high plasma renin levels. It is
clear that additional studies are required to determine whether the
angiotensinogen genotype is simply a marker for
hypertension and salt sensitivity of blood pressure or whether these
hemodynamic responses are in some way causally related
to altered products of gene expression in persons with the AA
genotype.
We can expect that future studies will not only uncover specific
genetic linkages with hypertension but will also provide information
about mechanisms by which genetic polymorphisms affect
physiological mechanisms that contribute to the
development of hypertension. From a clinical perspective,
identification of genetic markers for hypertension and for salt
sensitivity of blood pressure may have important implications for the
prevention and treatment of hypertension.
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Footnotes
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References
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Introduction
References