(Hypertension. 1999;33:1332-1337.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Linkage Analysis of Candidate Genes and Gene-Gene Interactions in Chinese Hypertensive Sib Pairs
From the Cardiovascular Division (T.N., K.L.) and the Channing Laboratory (X.X., J.R.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School; Department of Cardiology, The Children's Hospital, Harvard Medical School (T.N., K.L.); Program for Population Genetics (T.N., X.X., J.R.) and Division of Biological Sciences (T.N., X.X., J.R., K.L.), Harvard School of Public Health, Boston, Mass; Anhui Research Institute for Biomedical Sciences and Environmental Health, Anhui, China (X.X., Y.Z., Z.F.); Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio (H.J.C.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (K.L.).
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Abstract |
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Abstract—Previous studies of hypertension in humans and experimental animal models have identified a number of candidate genes that have since been implicated as possibly contributing to essential hypertension. Among them are the genes encoding angiotensinogen, renin, the ß- and
-subunits
of the epithelial sodium channel (ß/-ENaC),
-adducin, and kallikrein (KLK). To examine the role
of possible contribution of these genes in ethnic Chinese, as well as
the epistatic interaction among them, we studied a large cohort of
hypertensive sib pairs from China. DNA samples from 310 concordant
affected sibling pairs with hypertension were tested for linkage with
the use of excess allele–sharing algorithms based on genotyping
with highly informative GT-repeat microsatellite markers
localized in the immediate vicinity of the genes encoding
angiotensinogen, renin, ß- and
-ENaC, -adducin, and KLK.
Affected sib pair analysis conducted according to 3 different
methods (Statistical Analysis for Genetic
Epidemiology [S.A.G.E.]/SIBPAL,
MAPMAKER/SIBS, and affected pedigree member [APM] methods) revealed
no evidence for linkage of any of these genes to primary hypertension
in the population studied. Moreover, 2-locus sib pair linkage
analyses to test for gene-gene interactions among each possible
pair of candidate genes failed to yield any statistically significant
results. Our findings provide no support for a significant contribution
of the angiotensinogen, renin, ß/-ENaC,
-adducin, or KLK genes, alone or in concert, to the
pathogenesis of essential hypertension among Chinese. Our results
emphasize the possible role of ethnic differences for complex disease
genetics, as well as the need for large, well-characterized
investigations.
Key Words: renin • sodium channels • adducin • kallikrein • hypertension, essential • genetics • Chinese
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Introduction |
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Molecular variations in genes encoding blood pressure–relevant proteins, in concert with specific gene-environment effects and gene-gene interactions, are assumed to play a pivotal role in the pathogenesis of hypertension, given the well-established familial nature of this disorder. A number of candidate genes—derived from experimentation with experimental animal strains, from studies in rare, familial forms of hypertension, and from linkage and association studies in more heterogeneous cohorts—have recently received considerable attention. The majority of studies addressing the role of these genes in human essential hypertension have been of limited size, have primarily targeted whites, and have not considered gene-gene interactions. Given current knowledge of differential allele frequencies of many single nucleotide polymorphisms among different ethnicities, the importance of validating the data in these groups is obvious. We recently reported that among Chinese hypertensives, the angiotensinogen gene (AGT), the most thoroughly studied of hypertension candidate genes, was found not to contribute to blood pressure.1 In the present set of investigations we tested for possible gene-gene interactions between AGT and a number of other candidate genes that may shed light on this finding, and we report the results of linkage analyses for these additional genes and for all pairwise interactions among them.
Renin, the rate-limiting enzyme involved in the generation of the potent vasoactive hormone angiotensin II and therefore an attractive candidate for hypertension, has recently been reported to be associated with differential blood pressure in subjects of Afro-Caribbean heritage on the basis of a restriction fragment length polymorphism (RFLP) analysis.2 A study conducted among Taiwanese, enrolling 86 hypertensive and 107 normotensive subjects, demonstrated a significant association of the renin HindIII polymorphism with essential hypertension.3 In contrast, several previous case-control studies4 5 6 7 and linkage studies8 9 failed to support an etiologic role for the renin gene in human hypertension.
Liddle's syndrome (pseudoaldosteronism) is a hereditary form of
hypertension with autosomal dominant inheritance characterized by
severe hypertension, hypokalemia, and suppressed secretion of
aldosterone; it has recently been shown to be caused by
mutations in the genes encoding the ß- and -subunits of the
epithelial sodium channel (ß/-ENaC) that result in
excessive reabsorption of sodium in the distal
nephron.10 11 Although the mutations causing the
severe phenotype of Liddle's syndrome are very rare, it has
been suggested that less dramatic genetic variants of these genes may
be more frequently represented as one of the contributing
genes in polygenic forms of hypertension.12 Indeed, Baker
and colleagues13 recently demonstrated a significant
association of the T594M mutation of ß-ENaC
with hypertension in blacks. However, in a Japanese cohort of both
hypertensive and normotensive subjects, no mutations of the
carboxyl-terminal portion of ß-ENaC were
detected.14
Adducin, a heterodimer composed of an - and a ß-subunit, is a
cytoskeletal protein probably involved in cellular signal
transduction.15 Point mutations of the rat homologues of
the 2 genes have been linked to hypertension in the Milan rat
strain.16 Genetic variants of -adducin have been
postulated to affect kidney function by modulating the overall capacity
of tubular epithelial cells to transport ions.17 A number
of previous studies showed that the Gly460Trp
polymorphism of the -adducin gene is significantly associated
with hypertension,18 19 20 especially in relation to
salt sensitivity. However, no such association was found in 2 Japanese
populations.21 22
The kallikrein gene family encodes proteins with limited substrate specificity and high homology in their amino acid sequences. Two of these proteins may contribute to the regulation of blood pressure: tissue kallikrein, which specifically cleaves kininogens to generate kinins, and tonin, which cleaves angiotensin I and angiotensinogen to generate angiotensin II.23 24 A RFLP within the kallikrein gene (KLK) had previously been shown to cosegregate with increased blood pressure in recombinant inbred strains derived from the spontaneously hypertensive rat and the normotensive Brown Norway rat,25 and additional evidence points to a role of renal kallikrein in blood pressure regulation in animal models as well.26 Thus far, a limited number of small association analyses have failed to support a significant association of KLK polymorphisms with essential hypertension.27 28
None of these candidate genes has been studied in ethnic Chinese, and for none have initial results been replicated in large, well-characterized, family-based samples that avoid the possible selection bias inherent in case-control studies. Moreover, gene-gene interactions, although frequently postulated as being potentially of major impact, have only rarely, and never systematically, been taken into consideration. Using a cohort of 310 concordant affected sib pairs provided us with the opportunity to perform linkage analyses to address these issues.
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Methods |
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A detailed description of the study sample collection has been published previously.1 In brief, 310 hypertensive sib pairs (223 sib pairs, 21 sets of 3, and 4 sets of 4 affected siblings) were selected from the Zongyang and Huaining counties of Anhui province on the basis of data collected in a community survey of 20 216 individuals from the same area.29 Individuals aged >15 years without evidence of secondary forms of hypertension such as diabetes, hyperthyroidism, or glomerular nephritis were selected if their systolic blood pressure was
140 mm Hg
or diastolic blood pressure 90 mm Hg regardless of
treatment status. Five hundred fifteen (98%) of the 525
selected subjects had a previous history of physician-diagnosed
hypertension according to medical records, including information
about age of onset. In addition, 15 individuals who had a history of
hypertension and who were on antihypertensive therapy but who had blood
pressure <140 mm Hg systolic and 90 mm Hg
diastolic were enrolled. The study was approved by the
Institutional Review Committee of the Anhui Medical University, and all
study subjects gave informed consent. All the procedures followed were
in accordance with institutional guidelines. A questionnaire was
administered, and a screening examination was performed with the use of
standard protocols, as described previously.29
Blood Pressure Measurement
Triplicate blood pressure measurements were made by trained
nurses using a mercury-gravity manometer with appropriately sized
cuffs, as described previously.1
Phlebotomy
Forearm venous blood samples were then collected from each
subject by venipuncture, and plasma was subsequently
removed from the cell pellet by pipetting.1 All samples
were frozen at -85°C.
DNA Extraction
High-molecular-weight DNA (200 to 400 kb) was extracted with the
use of the QIAamp Blood Kit (QIAamp Inc), as described
previously.1
Microsatellite Polymorphisms
Genotyping for the GT-repeat microsatellite markers
D1S249 (renin), D4S43 and D4S126
(-adducin), D16S403 and D16S420 (ß- and
-ENaC), and D19S246 (kallikrein) was performed as
previously described.30 31 32 For each marker, 1 primer
was labeled at the 5' end with [32P]-ATP as
previously described,30 31 32 and polymerase chain reaction
was performed at annealing temperatures of 64°C (D1S249),
58°C (D4S43), 68°C (D4S126), 63°C
(D16S403), 55°C (D16S420), and 57°C
(D19S246) for 39 cycles. Reaction products were resolved
over denaturing sequencing gels containing 6% polyacrylamide,
8 mol/L urea, and 30% formamide and visualized by
autoradiography. Three control samples with known
genotype were run on each gel, interspersed with unknown
samples, to account for gel-to-gel variations. Scoring was performed by
2 independent observers, as described
previously.33
Statistical Analysis
A multianalytical approach encompassing several different
methods was used for the affected sib pair analysis.
S.A.G.E./SIBPAL Method
We used the Statistical Analysis for Genetic
Epidemiology (S.A.G.E.)/SIBPAL
program34 to perform a qualitative-trait linkage
analysis of D1S249, D4S43,
D4S126, D16S403, D16S420, and
D19S246. Given the sibships we have and appropriate
allele frequencies for the markers used, this
nonparametric method estimates the proportion (
) of
alleles identical by descent (IBD) that the hypertensive sib pair
shares at that locus. Because we only have 4 sets of 4 affected
siblings out of 248 sibships (1.6%), weighting by family size was
considered unnecessary.
MAPMAKER/SIBS Method
A multipoint linkage analysis was implemented with the
use of MAPMAKER/SIBS.35
Affected Pedigree Member Method
The affected pedigree member (APM) method is a model-free
approach that measures whether affected members of a pedigree have an
excess of allele sharing of the genetic markers
tested.36 The analyses were performed for
D1S249, D16S420, D16S403,
D4S126, D4S43, and D19S246 with the
use of 3 weighting functions designated as f(p): (1)
fA(p)=1, no weighting; (2)
fB(p)=1/
(p), intermediate weighting; and (3)
fC(p)=1/p, heavy weighting (p denotes the
allele frequency of each marker).
TWOLOC Method
The TWOLOC method37 38 is a multilocus linkage test
based on maximum likelihood that accounts for the interdependency of 2
putative susceptibility genes and evaluates the support for an
interaction between them. We used a modified version of TWOLOC that
maximized the likelihood using the FORTRAN subroutine MAXFUN of
S.A.G.E.33 Multilocus 2–1-0 IBD sharing probabilities for
linked and unlinked markers were calculated with the use of the
VITESSE39 and MAPMAKER/SIBS34 programs,
respectively.
Power Simulation Method
Power simulations were performed with the linkage strategies
described previously.40 41 42 For the D1S249
(polymorphism information content [PIC]=0.71, recombination
fraction 
=0.015), the D16S403 (PIC=0.65, =0.001), the
D4S43 (PIC=0.67, =0.013), and the D19S246
(PIC=0.73, =0.025), a 4-allele model with equal allele
frequencies (PIC=0.70), is used; for the D16S420 (PIC=0.75,
=0.000) and the D4S126 (PIC=0.79, =0.007), a
5-allele model with equal allele frequencies (PIC=0.77) is
used. The hypothesis being tested in our study is whether the genes
coding for renin, ß- and -ENaC,
-adducin, or kallikrein individually play a major role in the
causation of essential hypertension. Hence, a single-locus model was
used for each of the tested candidate genes, given the gene-specific
relative risk ratio, 
s. Power simulations were
performed for the total number of 310 affected sib pairs assuming
identity-by-state (scheme 1: information on pairs only).
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Results |
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The 525 study subjects, representing 248 sibships and 310 sib pairs, were exactly those subjects we previously investigated.1 They consisted of 335 males (64%) and 190 females (36%), and their clinical characteristics are shown elsewhere.1 Except for smoking, clinical parameters show very small variances, supporting the notion that the study population is relatively homogeneous. For all 6 markers studied, the distributions of genotype frequencies, determined from 1 randomly chosen individual from each sibship, were in agreement with Hardy-Weinberg equilibrium predictions.
Table 1 shows the results of linkage analyses using the S.A.G.E./SIBPAL program packages. No evidence for linkage was found for any of the markers studied. Likewise, APM analyses (shown in Table 2), using the recommended intermediate weighting function fB(p), showed no evidence of significant linkage for any of the markers tested. Single-locus linkage analyses using MAPMAKER/SIBS yielded z2:z1:z0 ratios not different from 0.25:0.50:0.25 for all markers tested.
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The maximum lod score results of a 2-locus general model that uses linkage algorithms to test for the presence of epistatic interactions among AGT and the candidate genes studied, as well as for each possible pairwise combination of these loci, are presented in Table 3. No increased allele sharing was observed among affected sib pairs for any 2 loci, ie, there was no excess of sharing 2 alleles IBD simultaneously at both loci or either locus tested in each pairwise constellation.
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Table 4 shows the power as a function of
gene-specific s according to the PIC value of
each of the 6 microsatellite markers tested (D1S249, D4S43,
D4S126, D16S403, D16S420, and D19S246), on
the basis of single-locus simulations assuming identity-by-state for
all the 310 affected sib pairs.
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Discussion |
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The primary goal of this family-based study was to test the possible epistatic modification of the previously reported association of AGT on hypertension by a series of additional candidate genes. In addition, we examined the contribution of these genes, which encode renin, ß/
-ENaC, -adducin, and kallikrein, to essential
hypertension in ethnic Chinese. To maximize the statistical power of
our investigation, we used a combination of approaches discussed below.
We found no support for a role of any of the genes, alone or in
interaction with one another, in the sample population studied.
The contribution of a given disease-contributing gene variant in common
complex disorders will vary among individuals with diverse
environmental exposures or at various developmental stages. Only if
select, genetically relatively homogeneous, large samples
are studied, in whom extensive documentation on confounding factors
exists (and thus the possibility to adjust for them), will there be
sufficient statistical power to successfully conduct and interpret such
studies. The sample size of our study (310 sib pairs) is, compared with
other similar studies, quite substantial. Moreover, our study included
a large majority of subjects whose blood pressure was in the extreme
upper tail of the distribution of the source population.1
Only 15 individuals who had normotensive blood pressures while being
treated with antihypertensive drugs, and who had extensive and
unambiguous documentation of pretreatment hypertensive values, were
included to avoid the loss of 19 sib pairs. These 15 patients
constitute <3% of the total sample and were also included in the
previously published report on AGT.1
Because of limited means of transportation, the Anqing population has a
quite stable base over thousands of years. Therefore, individuals of
this study are relatively homogeneous with regard to
ethnicity, socioeconomic status, and environmental, occupational, and
dietary exposures. These particular characteristics favor the presence
of relatively few genes/gene variants contributing to the disease and
thus increase the power of the linkage analysis. In addition,
our phenotype data—a common source of noise—are comparably
robust, because all blood pressure data were verified on entry in the
study. To quantify subjects' deviation from the mean of the blood
pressure distribution and thereby to confirm the relative severity of
their hypertension, we calculated residualized values, adjusting for
age, body mass index, gender, height, weight, cigarette smoking, and
other environmental covariates, and were able to show indeed that the
majority of our subjects fell into the distant upper tail of the
overall distribution (data not shown; see Reference 1 for
detail). For 2 of the candidate genes, ß/-ENaC and
-adducin, we extended and verified the analysis by inclusion
of an additional, highly polymorphic marker localized in close
proximity to each other.
Complex traits such as essential hypertension are usually not controlled by only a single disease locus but often involve multiple genetic and/or environmental factors that are assumed, at least to some extent, to be subject to specific gene-environment and gene-gene interactions. Only a small number of genetic studies of complex disorders have to date considered 2 marker loci simultaneously to detect linkage, undoubtedly because of, at least in part, the complexity and challenges of such analyses.43 44 With regard to hypertension, West and colleagues45 examined RFLPs of 5 genes (renin gene, haptoglobin gene, neuropeptide Y gene, and cardiac myosin ß heavy chain gene). There was no significant association between alleles at any of these loci and the presence of hypertension. Huggard and coworkers46 also investigated multiple candidate genes (AGT, insulinlike growth factor receptor gene, insulin receptor gene, angiotensin II receptor gene, elastin gene, and KLK), and no significant association of any of the markers used was found with hypertension status. Except for 1 limited attempt,44 none of these studies assessed the joint effects of 2 (or >2) candidate loci simultaneously.
Classic genetic statistical analysis typically investigates only a single marker locus, accounting for the effects of additional loci through assumptions of reduced penetrance or phenocopy. Recently, a number of new methods have been proposed to investigate the joint action of 2 genes in a disease by using information on 2 genetic markers simultaneously.37 47 48 49 The parametric, 2-locus lod score method of Schork et al48 requires the specification of the mode of inheritance and involves a large burden of computation. Affected sib pair tests are computationally simple and do not require an explicit specification of the disease model. In the past, however, use of these tests has been restricted to data with a single marker locus. Cordell and colleagues37 extended the maximum lod score method of Risch,42 which allows the simultaneous detection and modeling of 2 disease loci unlinked to each other but potentially interacting in their linkage to affection status. Using simultaneous information on 2 markers can lead to increased power for detection of an effect over using a single-locus method if the effect of the 2 genes is not multiplicative.43 49 We have performed the sib pair linkage analyses by modeling 2 candidate loci at the same time for all marker pairs, and no significant findings were obtained. In addition, single-point approaches (APM, S.A.G.E./SIBPAL, MAPMAKER/SIBS) were also performed in our affected sib pair linkage analyses. The results of our analyses remain consistent whether or not weighting for rare alleles is used; this raises our level of confidence in our data.
As documented previously,1 we were in the unique position,
in the Anhui population, to have access to a contemporaneously
established, large, cross-sectional database collected in 20 216
subjects from the same province 1 year earlier.29 This
allowed us to validate our selection of probands and to determine a
population-specific index of heritability of hypertension for direct
assessment of the power of our study. Thus, using the 90th percentile
of the distribution of residuals (adjusted for blood pressure–relevant
covariates such as age, gender, height, socioeconomic status, exercise,
and smoking) as cutoff for defining hypertension, we found the sibling
recurrent risk ratio, s, to be
2.4.1 Because our study yields negative results, it raises
the concern of statistical power. The most critical factor in
determining power is the PIC.42 Four equally frequent
alleles yield a PIC of 0.70, and 5 equally frequent alleles
correspond to a PIC of 0.77, both reasonable for the markers we used.
For the total sample, the estimated power was >85% with respect to
any given marker tested (Table 4). However, because the
gene-specific sibling recurrent risk s for
each of the hypertension-causing genes is less than the aggregate
recurrent risk s, total (it is assumed that
given N genes contributing to essential
hypertension, s,
total=s,1+s,2+
... +s, N under the additive model), the
actual power of our sample may be less than the power derived from our
simulation algorithm for any given gene of interest, because we have to
assume a polygenic etiology.
In summary, we found no interaction between the AGT locus
and the genes encoding renin, ß/-ENaC, -adducin, and
KLK loci with respect to essential hypertension in Chinese,
and neither was any of these candidate genes linked to the disease. Our
results demonstrate that if genetic variants of these genes indeed
contribute to essential hypertension, then their role may depend
importantly on ethnic background. Thus, our findings may indicate
important etiologic diversity in the genetic spectrum of primary
hypertension.
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Acknowledgments |
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This work was supported in part by a research career development award (K04-HL03138-01) from the National Heart, Lung, and Blood Institute (to Dr Lindpaintner). Some of the results of the sib pair linkage analyses were obtained by use of the program package S.A.G.E., which is supported by a US Public Health Service Resource grant 1 P41 RR03655 from the Division of Research Resources.
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Footnotes |
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Reprint requests to Klaus Lindpaintner, MD, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115-6195.
Dr Lindpaintner and Dr Xu contributed equally to this work.
Received September 14, 1998; first decision October 9, 1998; accepted February 10, 1999.
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