Mode of Impact of Genetic Determinants of Hypertension in People of African Descent
Date
2006-11-10T11:37:30Z
Authors
Ngwenchi, Nkeh Benedicta
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Abstract
Blood pressure (BP) is a heritable trait. However, the loci responsible and the
mechanisms by which these genes determine BP are uncertain. Based on widely
published data regarding frequent phenotypic characteristics that exemplify essential
hypertension (EHT) in persons of African ancestry, in the present thesis I explored the
role of gene candidates most likely to contribute to BP in this group. In this regard a high
frequency of persons of African descent experience increases in BP in response to an
enhanced salt intake (salt-sensitive hypertension). In addition, many patients of African
origin with EHT fail to respond to inhibition of angiotensin-converting enzyme (ACE)
with an appropriate decrease in BP, a factor that cannot be explained entirely on the basis
of reduced plasma renin levels in this group. Thus, I evaluated the role of several gene
variants that could influence either renal salt handling or the activity and effects of the
renin-angiotensin system on BP in subjects of African ancestry.
Although the angiotensinogen (AGT) gene has at least 3 variants in the promoter
region that influence angiotensinogen expression and which occur with a remarkably high
frequency in populations of African ancestry, their role in this group is still controversial.
To-date, interactions between these variants have not been considered. Using a casecontrol
study design in a sample of 1325 subjects, as well as association analysis with 24
hour ambulatory BP (ABP) values in 626 hypertensives, I confirmed that an independent
effect of functional AGT gene variants on the risk for EHT or 24 hour ABP was weak at
best. Importantly, however, interactions between the -20A C and -217G A variants
were noted to strongly impact on the risk for EHT as well as ABP. Furthermore,
interactions between the -20A C and -217G A variants played a major role in
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contributing toward the variability of ABP responses to ACE inhibitors, but not calcium
channel blockers in this population group, with genotype determining whether or not
ACE inhibitor responses occurred.
Although the 825C T polymorphism of the guanosine triphosphate (G) protein
3 subunit (GNB3) gene influences the activity of a substance that modifies renal salt
handling, namely the Na+/H+ exchanger, its impact in hypertensives of African descent is
controversial. In the present thesis I confirmed in a large sample that the GNB3 variant
was not associated with the risk for EHT or ABP values in subjects of African ancestry.
However, because the activity of the exchanger is enhanced in obesity I hypothesised that
the GNB3 gene variant could mediate a clinically relevant BP effect by modifying the
impact of body size on BP (type I or II genetic effect). Indeed, GNB3 genotype proved to
be a strong determinant of the impact of body size on systolic BP values, with genotype
determining whether or not the effect occurred.
The epithelial sodium channel (ENaC) and atrial natriuretic peptide (ANP) have
an important influence on renal salt handling. The T594M polymorphism of the -subunit
of the ENaC gene only exists with a relatively high frequency in subjects of African
ancestry. Previous studies conducted in this population group in relatively small samples
have indicated that the ENaC and ANP gene variants determine BP in subjects of African
descent. In a larger sample of subjects of African descent I demonstrated that the T594M
polymorphism of the ENaC gene has no impact on BP in this population group. However,
my results suggest that the ANP gene may be a candidate worthy of further study.
In conclusion, the results described in this thesis provide evidence that lends some
clarity to the role of likely gene candidates for BP control in people of African descent.
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Importantly, data from this thesis suggest that interactions between functional variants of
specific loci (e.g the AGT gene), and clinically relevant type I or II genetic effects (no
independent actions, but modifier gene effects, e.g, GNB3) should be considered before
excluding loci as playing an important role in BP control. Moreover, this thesis provides
the first substantial data to indicate that gene variants determine the variability of BP
responses to pharmacological agents in hypertension in this population group.
Description
Faculty of Health Sciencs
School of physiology
0010633J
bnkeh@uycdc.uninet.m
Keywords
Hypertention, African descent, Polymorphisms, Ambulatory, Blood pressure