From INSERM U358, Hôpital Saint-Louis, Paris, France.
Correspondence to Florent Soubrier, INSERM U358, Hôpital Saint-Louis, 1 av Claude Vellefaux, 75475 Paris cedex 10, and Laboratoire de Génétique Moléculaire, Hôpital Tenon, 4, rue de la Chine, 75970 Paris cedex 20, France. E-mail florent.soubrier{at}tnn.ap-hop-paris.fr
The candidate gene
approach allows several genes responsible for several monogenic forms
of hypertension to be identified, owing to an accurate knowledge of the
clinical and biological phenotypes of these diseases, to the
judicious choice of candidate genes whose functions are tightly related
to the phenotypes, and to the mendelian segregation of these
diseases in large pedigrees.1 However, in humans,
no gene has been definitively established as a source of genetic
variance of BP, corresponding to the putative major gene suggested by
some segregation analyses2 3 or as a
predisposing gene to hypertension. Even if some data indicate a
possible role for the angiotensinogen (AGT) gene
and if associations are found with other genes, conflicting results are
found in the literature, and no clear physiological
effect on BP has been associated with a functional variant. In the rat
model of hereditary hypertension, although >10 loci linked to BP have
been identified in various strains, no single gene has yet been
identified.
In this issue, two articles report data suggesting a linkage
between the ACE locus and DBP or mean
BP.4 5 In both studies, several hundred families
were studied, and these were not selected for a particular level of BP
but were chosen to represent large samples of the population.
The statistical methodology used to quantify, by a family approach, the
effect of the ACE locus on BP is slightly different in the
two studies. The study by O'Donnell et al4 used
a classic approach through the use of the SIBPAL program to
test for linkage by relating the quantitative or qualitative trait
difference to genotype resemblance in sibpairs. Fornage et
al5 used a methodology aimed at quantifying that
part of the variance of the quantitative trait (ie, BP) that is
determined by the marker locus. The markers used at the ACE
locus were the same in the two studies, a highly polymorphic and
complex tandem repeat (dinucleotide and
tetranucleotide repeats) marker located on the
GH gene, for which no recombination is observed with the
ACE gene in humans. The I/D polymorphism of the
ACE gene was also used by O'Donnell et al in the linkage
and the association analyses.
The study of O'Donnell and colleagues shows a linkage of the
ACE locus markers in the entire panel of families. After
subdivision according to sex, there was a marginally significant
linkage with diastolic BP in male (P=0.02 and
P=0.04 for ACE and hGH, respectively)
but not in female sibling pairs. Surprisingly, the nominal P
value for linkage was more significant with the less informative
marker, in this case, the I/D polymorphism, both in male-only and
sex-pooled analyses. A borderline P value
(P=0.047) was obtained for linkage of the ACE
locus to hypertension as a dichotomous variable, but only in
men.
Fornage et al5 similarly found that the
ACE locus is also linked to DBP and mean BP in adolescents,
with a mean age of 15 years. Analysis of the whole group gave
results that were not very different for the ACE marker
(P=0.04) from what was obtained with the AGT
(P=0.06) or the angiotensin II type 1 receptor
(AT1) (P=0.10) marker. The analyses of
siblings having a family history of hypertension and the
analyses of male sibships led to more contrasting results
obtained with these genes; the variance explained by the ACE
gene reached 30% for DBP and mean BP, with P<0.005. These
results raise two main linked questions. Are these results sufficient
to indicate that there is a gene determining the level of BP, mainly
diastolic, at the ACE locus? If there is a gene,
is it the ACE gene itself?
To the first question, a rather prudent reply would be given if these
two studies were considered independently, because the linkage data are
far from reaching robust statistical significance and were obtained
mainly after stratification into subgroups defined a posteriori. Low
power to detect linkage might be expected, because the studies were
undertaken in normotensive families. The marginal significance levels
obtained after subdivision of the data by sex is compensated for in
part by the fact that these two independent studies converged on
similar results.
In addition to these data, other lines of argument support the idea
that this locus might contain a gene for BP. In 1991, two groups
described a major locus on chromosome 10 for high BP in a cross
(BP/SP1) between stroke-prone spontaneously hypertensive rats (SHR/SP)
and Wistar-Kyoto rats (WKY) that is homologous to the ACE
locus, which is on chromosome 17 in humans.6 7
Similar results were found by others using different strains of
hypertensive rats.8 These results were observed
in the rat model of hereditary hypertension and encouraged the
investigation of this locus in human hypertension. An initial study by
Jeunemaitre et al,9 who used the hGH
microsatellite in a limited number of moderately hypertensive families
was negative. However, in a recent article, Julier et
al10 extensively studied the ACE locus
by using several microsatellite markers in a large panel of
hypertensive families from France and the United
Kingdom.10 In this study, the hGH
marker gave strongly significant results for linkage to hypertension
when considered as a qualitative trait, by both
nonparametric methods of affected sibpair analysis
and parametric methods that assumed a model for the disease.
Other microsatellite markers, such as D17S934, close to the anion
exchanger 1 gene and located at
It seems that in the case of the ACE locus, a monogenic form
of hypertension might help to identify the gene. A genome-wide linkage
search was performed for a dominantly inherited form of hypertension,
type II pseudohypoaldosteronism, or Gordon's syndrome. A linkage was
found with two different loci, one on chromosome 1 and the other on
chromosome 17, in different sets of families. The linkage to these two
different loci is a consequence of the locus
heterogeneity of this syndrome, but no phenotypic
differences were found between families linked to the different
loci.11 The chromosome 17 locus is located
precisely between markers D17S579 and D17S793, which gave the most
significant results for linkage to essential hypertension in the study
of Julier et al.10
Thus, three types of argument drawn from human monogenic hypertension,
from studies in essential hypertension or in normotensive subjects, and
from the rat model of hereditary hypertension point to the
ACE locus on human chromosome 17, or its homologous rat
locus on chromosome 10.
Is the ACE gene the actual gene responsible for the effect
on BP variance, or is it another gene located in the close vicinity? Or
should we consider the possibility of two different genes at the same
locus, one of them being the ACE gene? The results
presented in the two articles are linkage data, which are able
to detect an effect due to a gene located at a distance from the marker
used, even if the power to detect linkage decreases when the genetic
distance between the marker and the locus increases. A productive
way to map genes for a common disease is to search for linkage
disequilibrium, which consists of the preferential association of the
marker allele with the disease allele. When linkage
disequilibrium is observed between the marker and the disease, it
usually indicates that the marker is only a short distance away from
the gene.
Linkage disequilibrium studies are also presented in the
article of O'Donnell et al, who looked at the odds ratio for
hypertension in men or women according to their ACE
genotype and the association between ACE
genotype and BP. Results become marginally significant when
stratification by sex is done, because only the data for the male group
give statistically significant results. Neither females separately nor
the whole group gave significant results. The D allele
of the I/D polymorphism was found to be associated with an
increased risk of hypertension in males only, and there was a
significant increase in age-adjusted DBP with the number of
D alleles, again in males only. It is puzzling that the
risk associated with the D genotype does not
increase in a group defined by more severe hypertension, which would be
expected from a gene that predisposes to hypertension. Also surprising
is that the association of the I/D genotype with
diastolic BP was no longer significant after adjustment for
antihypertensive treatment or other covariates.
Published results describing an association between ACE
genotype and BP are as numerous as those that have not found
such an association. In control subjects of a large case-control study
on myocardial infarction, there was no effect associated with the
I/D genotype.12 This was also
the case in a study of healthy adults and children; ie, there was no
association of the I/D genotype with
BP.13 Nevertheless, weakly significant
correlations between SBP and DBP and plasma ACE level were found in
children in this study, and in male adults in another study by
Schunkert et al.14 Correlations of BP with plasma
ACE levels in these studies might have origins other than the
ACE gene itself.
ACE is not considered to be the limiting step for
angiotensin II generation, at least for circulating
angiotensin II.15 Moreover, the
increase in BP induced by angiotensin I infusion in normal
subjects was not influenced by the I/D genotype, at
least in one study performed in subjects during acute renin
blockade.16
In mice, tandem duplication of the ACE gene by homologous
recombination was performed by Krege et al.17 The
presence of four copies (instead of two, normally) of the
ACE gene doubled plasma ACE levels but did not raise BP, a
result that contrasts with the BP rise that was observed after
duplication of the AGT gene in mice.18
If the rat hypertension gene found in the homologous region is the same
as that whose existence is presumed in humans (a possibility that is
far from proven), some arguments drawn from experiments in the rat do
not favor the ACE gene. A congenic line, in which an
Is there any argument drawn from physiological
observations that these putative genes, drawn from different sets of
data, are indeed only one? This hypothesis implies that different
mutations of the same gene would be able either to lead to a severe
form of human hypertension, with mild hyperkalemia and
metabolic acidosis, or to cause a BP increase as observed
in humans, even within the normal range of BP, or in rats. Such gradual
clinical phenotypes have been described for severe monogenic
diseases such as cystic fibrosis, for which mutations causing mildly
altered phenotypes have been
observed.20
Common essential hypertension, as well as Gordon's syndrome, is
sensitive to different degrees to thiazide diuretics, which act
on the thiazide-sensitive sodium/chloride cotransporter of the distal
convoluted tubule. A defect of this gene is responsible for Gitelman's
syndrome and its associated hypokalemia and metabolic
alkalosis, which resembles a "mirror" syndrome to Gordon's
syndrome.21 In this case, the beneficial effect
of these drugs is not sufficient to designate the culprit gene, because
the cotransporter gene maps to chromosome 16. In hypertension and even
more markedly in Gordon's syndrome, thiazide diuretics might
correct an excess sodium or chloride reabsorption, which more likely
results from a gain in function of an ion channel or transporter.
At this point, it would be interesting to analyze the large
panels of families presented in the two articles with respect
to several markers at the ACE locus. It is also important to
identify all genes present in the region and to carefully select
candidate genes. The sequence of this short list of genes will have to
be compared between normal subjects, hypertensive subjects, and
patients from Gordon's syndrome families, with this syndrome linked to
the chromosome 17 locus. Similarly, the sequences of these genes will
have to be compared between SHR/SP and WKY rats. The time required to
achieve this substantial amount of work separates us from the discovery
of this gene foretold, which likely has major importance for BP
regulation.
Selected Abbreviations and Acronyms
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
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© 1998 American Heart Association, Inc.
Editorial
Blood Pressure Gene at the Angiotensin I–Converting Enzyme Locus
Chronicle of a Gene Foretold
Key Words: Editorials • chromosomes • pseudohypoaldosteronism • linkage disequilibrium • genetics
18 centimorgans (cM) from the
hGH marker, gave more significant results for linkage. The
most significant test statistics were obtained by using the D17S934
marker in combination with the GH marker in a multilocus
linkage analysis. 6-cM
region of the chromosome 10 locus from the SHR/SP strain was
introgressed in WKY rats, allowed the BP/SP1 locus to be more precisely
characterized.19 Indeed, analysis of the
data under a two-locus model leaves open the possibility of two
distinct quantitative trait loci (QTL) in this region. According to
this analysis, one locus for salt-load SBP would be closely
linked to ACE/GH, and the other, linked to basal
SBP, would be located 20 cM toward the centromere. Candidate genes
in the homologous human region were investigated, such as anion
exchanger I, but no sequence abnormality was detected, at least by
indirect methods, in patients with Gordon's syndrome linked to the
chromosome 17 locus.11 However, several other
genes, which have to be identified and explored, also exist in this
region.
ACE
=
angiotensin-converting enzyme (gene)
(D)BP
=
(diastolic) blood pressure
(h)GH
=
(human) growth hormone (gene)
I/D
=
insertion/deletion
SBP
=
systolic blood pressure
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