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(Hypertension. 1997;30:773-776.)
© 1997 American Heart Association, Inc.
Articles |
Essential Hypertension in African Caribbeans Associates With a Variant of the ß2-Adrenoceptor
From the Department of Internal Medicine Krankenhaus der Barmherzigen Brüder and Teaching Hospital of the Karl Franzens University Graz, Austria (P.K., A.B., F.S.); the Departments of Clinical Pharmacology (S.K., M.C.) and Chemical Endocrinology (J.T., A.J.L.C.), St Bartholomew's Hospital, West Smithfield, UK; and the Ministry of Health of St Vincent and the Grenadines, Kingstown, West Indies (P.D.).
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Abstract |
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Abstract Populations of West African ancestry dwelling in Western communities exhibit greater prevalence of human essential hypertension and higher rates of end-organ damage. The sympathetic nervous system influences cardiac output, vascular tone, renal sodium reabsorption, and renin release and could be implicated in enhanced vascular responsiveness observed in African hypertensives. Such an effect could arise from genetic variants that alter agonist response of
-adrenoceptors, leading to enhanced vasoconstriction, or attenuate
ß2-adrenoceptor–mediated vasodilatation. Indeed, there
is evidence of a blunted vasodilator response to the ß-agonist
isoprenaline in African Americans. A variant of the
ß2-adrenoceptor gene that encodes glycine rather than
arginine at position 16 (Arg16
Gly) has been shown to confer
exaggerated agonist-mediated receptor downregulation, which might
attenuate vasodilator response. One hundred thirty-six unrelated
hypertensives and 81 unrelated normotensives of African Caribbean
origin were identified from primary care on the island of St Vincent.
Genomic DNA from these subjects was analyzed for the presence
of the Gly16 and Arg16 alleles by using an allele-specific
polymerase chain reaction method. We report strong support for
association of the prodownregulatory glycine 16 variant of the
ß2-adrenoceptor gene with hypertension in African
Caribbeans from St Vincent and the Grenadines
(
2=18.9, P=.000014, 1 df).
This observation, coupled with reports of attenuated vasodilator
responses to ß-agonists among people of West African ancestry, may
provide a mechanism for enhanced vascular reactivity and identify a
candidate gene for hypertension in this ethnic group.
Key Words: ß2-adrenoceptor gene • hypertension • genetics • African ethnicity
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Human essential hypertension is thought to arise from an interaction between susceptibility genes and environmental factors. To date, investigation of the genetic basis of hypertension has largely focused on candidate genes from the renin-angiotensin system. Indeed, there is support for linkage and association of the angiotensinogen gene to hypertension in two different populations of white European origin and one population of African Caribbean ethnicity.1 2 3 The sympathetic nervous system represents a second important regulator of blood pressure through alterations in vascular responsiveness, renin release, renal sodium handling, and cardiac output.4 Accordingly, genetic variation in either the
-adrenoceptor, leading to enhanced
vasoconstriction, or ß2-adrenoceptors, leading to
attenuated vasodilatation, might be important for increasing total
peripheral resistance and hence blood pressure. In
addition, evidence from cultured skin fibroblasts indicates that the
expression of ß2-receptors in normotensive white
Europeans with sodium-responsive blood pressure is less than half of
that observed in salt-resistant subjects.5 6 This
observation provides a potential link between sodium sensitivity and
the sympathetic nervous system. The greater prevalence of hypertension
and end-organ damage, such as stroke and renal disease, in populations
of West African ancestry has prompted speculation that there may be
ethnic differences in the genetic basis of high blood
pressure.7 This hypothesis is supported by observations in
people of African origin that the blood pressure response to sodium
loading or mental and physical stress is enhanced.8 9 The
human ß2-adrenoceptor is a member of the guanosine
protein–linked, seven-transmembrane-domain–receptor superfamily and
has been extensively studied in terms of
physiological and pharmacological
functions.10 An amino-terminal variant that encodes
glycine instead of arginine at position 16 (Arg16Gly) within the
receptor exhibits exaggerated agonist-mediated receptor downregulation
and could therefore lead to enhanced vascular
reactivity.11 12 In this study, we tested whether there is
an association between the Arg16Gly variant of the
ß2-adrenoceptor and essential hypertension in African
Caribbeans from St Vincent and the Grenadines. |
Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Population
The subjects reported here (Table 1
) were recruited from semirural primary
care clinics on the island of St Vincent3 after ethical
approval from the Ministry of Health of St Vincent and the Grenadines.
The subjects were of African ancestry by grandparental and parental
ethnicity. During screening, we identified 136 unrelated hypertensives
who had a positive family history of hypertension and whose
hypertension was defined by diastolic blood pressure
greater than 95 mm Hg or by receipt of antihypertensives with
documentary evidence of diastolic blood pressure greater
than 95 mm Hg. Simultaneously, we identified 81
unrelated normotensives who had a negative family history of
hypertension and whose diastolic blood pressure was less
than 85 mm Hg. Genomic DNA from these subjects was extracted
using phenol-chloroform purification.
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Genetic Analysis
Genotyping of the ß2-adrenoceptor variant was
cross-checked by an individual who was unaware of the subject's
phenotype, and all genotypes were repeated twice to
confirm assignment. The polymorphism of the
ß2-adrenoceptor encoding the receptor amino acid at
position 16 (Gly16 or Arg16) of the ß2-adrenoceptor was
delineated using an allele-specific polymerase chain reaction (PCR)
approach.
PCR reactions were carried out in a volume of 25 µL using 300 ng of
genomic DNA; the primer pairs were:
5'-CTTCTTGCTGGCACCCAATA-3' (sense) and
5'-ACAATCCACAC CATCAGAAT-3' (antisense) or the same antisense primer
and 5'-CTTCTTGCTGGCACCCAATG-3' (sense). Use of these
primers resulted in a product with a molecular size of 452 base
pairs. One international unit of Dynazyme (Dynal) was used with
reaction buffers supplied by the manufacturer and 1.5
mmol/L magnesium chloride. Amplification was over 30 cycles at
95°C for 30 seconds, 68°C for 35 seconds, and 72°C for 35
seconds. Seven microliters of the PCR reactions was then
electrophoresed on 1.5% agarose gels and visualized with ethidium
bromide staining and ultraviolet illumination. Each DNA sample was
analyzed twice, and direct sequencing of the region containing
Arg16Gly variant was undertaken using Thermus aquaticus
fluorescent cycle sequencing (Taq FS sequencing kit,
Perkin-Elmer) on an automated (ABI 377) sequencer (Applied Biosystems)
to confirm the robustness of the genotypes in 18
individuals.
Statistical Analysis
The association of the Arg16Gly polymorphism and
essential hypertension was tested by comparison of the distribution
of genotypes and alleles with the 2
test. The relative risk of hypertension associated with allelic
variation at the ß2-adrenoceptor gene is expressed in
terms of an odds ratio with 95% confidence limits, which was computed
according to the method of Miettinen with the application of
Yates' correction.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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One hundred thirty-six unrelated hypertensives and 81 unrelated normotensives of African Caribbean origin were identified from primary care on the island of St Vincent (demographic data are summarized in Table 1
). Genomic DNA from these subjects was analyzed for the
presence of the Gly16 and Arg16 alleles by using an
allele-specific PCR method. The distribution of
ß2-adrenoceptor alleles did not conform to
Hardy-Weinberg equilibrium in this study. However, the careful
ascertainment of hypertensive and control subjects from the same
population, coupled with our published observations of Hardy-Weinberg
equilibrium in the same population with several diallelic markers at
other loci, makes selection bias in our cohorts highly
unlikely.3 13 In addition, all genotypes were
repeated twice for confirmation, and these results were cross-checked
in 18 individuals by direct sequencing, which confirmed our data in all
cases and minimized the risk of laboratory error during genotyping.
There was marked disequilibrium in the distribution of
genotypes (Gly16/Gly16, Gly16/Arg16, and Arg16/Arg16) between
normotensives and hypertensives (2=14.6,
P=.0007, 2 df), with the number of Gly16
homozygotes markedly increased in the hypertensive subjects (Table 2). The frequency of the Gly16 allele
in the hypertensive patients was 0.85 and in the normotensive controls
0.66 (2=18.9, P=.000014, 1
df). The relative risk of hypertension associated with
alleles of the ß2-adrenoceptor gene was increased,
with a corrected odds ratio of 2.74 (95% confidence limits, 1.72
to 4.36).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we have demonstrated association of a variant within the ß2-adrenoceptor gene with essential hypertension in African Caribbeans. The frequency of the prodownregulatory Gly16 allele of the ß2-adrenoceptor gene is considerably higher in hypertensives than in normotensives. This observation may account for ß2-adrenoceptor regulation in resistance vessels and might explain the blunted forearm vasodilatation that has been reported in normotensive African Americans in response to infusion of the ß-adrenoceptor agonist isoprenaline.14 Such attenuation of the vasodilatory response in people of West African ancestry could contribute to the increase in total peripheral resistance in response to sympathetic stimulation by mental or physical stress and may elevate blood pressure.9
This result is very unlikely to be due to ethnic admixture or a population-stratification artifact, since the distribution of other diallelic polymorphisms and blood-group antigens within St Vincent is very similar to that observed in West Africans and African Americans.3 15 Furthermore, the hypertensives and normotensives in this study were identified from the same semirural clinics. The normotensive subjects were younger in mean age than the hypertensives but were recruited from decades in which hypertension is manifest. Since hypertension has a variable age of onset, it remains possible that some of the normotensives may subsequently develop hypertension, but this would only serve to dilute any association with the trait. Although the numbers of each sex were not equal in each group, it is unlikely that there is a sex-specific influence on the distribution of this intragenic variant of ß2-adrenoceptor, since the gene is located on chromosome 5.
Evidence for the regulatory influence of the Arg16Gly variant
of the ß2-adrenoceptor gene stems from transfection
experiments in Chinese hamster (CHW-1102) fibroblasts,12
which indicate identical affinities of either variant for isoprenaline
and adrenaline. In contrast, after prolonged exposure to isoprenaline,
the Gly16 allele exhibited enhanced agonist-mediated receptor
downregulation.12 Further support for this finding emerges
from quantitative in vivo assessment of pulmonary
ß-adrenoceptor response to the ß2-agonist salbutamol,
demonstrating that the Gly16 variant associates with enhanced
agonist-induced receptor downregulation.16 Indeed, the
Gly16 allele has been recently associated with nocturnal
asthma,17 and therefore, diminished receptor number may be
an important genetic factor in that asthmatic phenotype.
Additional support for a role of the
ß2-adrenoceptor gene in hypertension arises from a recent
report of association of a restriction fragment length polymorphism
(RFLP) at this locus with hypertension in African
Americans.18 Although the Arg16Gly variant, which may
have functional influences, was not studied by that group, it is
probable that the RFLP alleles are in linkage disequilibrium with
this coding alteration.
The distribution of ß2-adrenoceptor
genotypes in this study deviates from Hardy-Weinberg
equilibrium. This law describes the expected distribution of
genotypes in a population under the assumptions of random
mating, with no change in genotype frequencies from one
generation to the next and without mutation, migration, or natural
selection. When deviations from this equilibrium arise, the possibility
of selection bias in establishing the study or incorrectly assigned
genotypes due to laboratory error must be considered. As we
have indicated, previous studies in this population have conformed to
Hardy-Weinberg criteria, and we have genotyped all subjects
twice, which makes these possible explanations less
likely.3 13 Interestingly, the distribution of RFLP
genotypes of the ß2-adrenoceptor reported
previously also deviates from Hardy-Weinberg equilibrium in a
population of African Americans.18 Furthermore, in the
same report from the same population, the genotypic distribution at the
2-adrenoceptor locus did conform to Hardy-Weinberg
criteria. In tandem with our data, this finding may reflect the
relationship of genotypes at the ß2-adrenoceptor
locus with hypertension rather than population bias or laboratory
error.18
This study offered 95% power to demonstrate a change in the distribution of the glycine allele from 0.66 in the normotensives to 0.85 in the hypertensives; P=.0002. In spite of the power of this study and the observations reported, it is necessary to remain cautious about these results until they are replicated in other populations of West African ancestry.
In conclusion, essential hypertension in African Caribbeans is associated with an increased frequency of the Gly16 allele of the ß2-adrenoceptor. This variant may predispose to essential hypertension by conferring enhanced agonist-mediated receptor downregulation and represents an additional candidate for the genetic basis of this complex trait.
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Acknowledgments |
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This work was supported by the Joint Research Board of St Bartholomew's Hospital, the Mason Medical Foundation, the Fellowship of Postgraduate Medicine, St Bartholomew's Hospital Special Trustees, and the Fonds zur Förderung der wissenschaftlichen Forschung, Austria (SFB 007 "Biomembranes"). We thank the people of St Vincent and the Grenadines.
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Footnotes |
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Reprint requests to Dr Peter Kotanko, MD, Department of Internal Medicine Krankenhaus der Barmherzigen Brüder and Teaching Hospital of the Karl Franzens University Graz, Marschallgasse 12, A-8020 Graz, Austria.
Received January 14, 1997; first decision February 10, 1997; accepted April 1, 1997.
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