(Hypertension. 1996;27:308-312.)
© 1996 American Heart Association, Inc.
Articles |
Genetic and Biochemical Factors Associated With Variation in Blood Pressure in a Genetic Isolate
From the Departments of Medicine (R.A.H., P.W.C.), Clinical Biochemistry (R.A.H., P.W.C.), and Biochemistry (P.W.C.), St Michael's Hospital, University of Toronto, Ontario, and School of Nursing, University of Victoria, British Columbia (J.H.B.), Canada.
Correspondence to Robert A. Hegele, MD, DNA Research Laboratory, St Michael's Hospital, 30 Bond St, Toronto, Ontario, M5B 1W8, Canada. E-mail robert.hegele@utoronto.ca.
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Abstract |
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Abstract We previously found an association between blood pressure and genetic variation of angiotensinogen in Canadian Hutterites. We hypothesized that variation in other candidate genes would also be associated with variation in blood pressure. We included genotypes of 12 candidate genes, along with clinical features and biochemical variables as covariates in an association analysis. We found that sex and body mass were significantly associated with variation in both systolic and diastolic blood pressures. We found that genotypes of APOB codon 4154 and AGT codon 174 were significantly associated with variation in systolic blood pressure. We found that genotypes of APOB codon 4154, AGT codon 174, and F7 codon 353 were significantly associated with variation in diastolic blood pressure. We found a significant association between age and variation in systolic but not diastolic blood pressure. We found a significant association between plasma apo B concentration and variation in diastolic but not systolic blood pressure. The association of genomic variation with resting blood pressure is consistent with the existence of important structural elements within or proximal to some genes in lipoprotein metabolism, the renin-angiotensin system, and the coagulation cascade. The association between plasma apo B concentration and diastolic blood pressure suggests that these traits may share some determinants.
Key Words: genetics, biochemical • hypertension, genetic • lipid metabolism
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Complex quantitative traits such as BP are influenced by genetic and nongenetic factors.1 Candidate genes that determine BP variation include those whose products have a direct role in vascular biology, such as components of the renin-angiotensin system.1 2 However, other candidate genes for BP variation, such as those with products that regulate lipoprotein metabolism, have been suggested by the clinical observation of familial clustering of hypertension with metabolic disturbances such as hyperlipidemia.2 3 A general association of lipid abnormalities with essential hypertension has been reported in some epidemiological studies.4 5 We previously reported that amino acid variation of the angiotensinogen gene (AGT) at codon 174 was significantly associated with variation of systolic BP in male North American Hutterites.6 We also reported significant associations between candidate genes whose products act in lipoprotein metabolism and variation in plasma lipoproteins in these Hutterites.7 8 9 Many of the candidate genes in lipoprotein metabolism that we studied in the Hutterites have also been suggested to be candidates for BP variation.2 Thus, we saw an opportunity to identify associations between these candidate genes in lipoprotein metabolism and variation of BP in this unique study sample.
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Methods |
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Study Subjects
The Hutterite Brethren are an Anabaptist sect with approximately 30 000 members who live in Western Canada and the adjacent United States. The characteristics of this genetic isolate are described elsewhere.6 7 8 9 Hutterites have an agrarian lifestyle and live on communal farms called colonies.6 Although the incidence of CHD in the Hutterites is unknown, the prevalence of risk factors appears to be comparable to that found in other populations.10 Subjects from 21 colonies of Alberta Hutterites took part in the Canadian Heart Health Survey of CHD risk factors.11 12 Physical examination included determination of BMI defined as weight/height2 (kg/m2) and four separate BP determinations. All patients answered a questionnaire indicating whether they currently used medication for hypertension. Plasma samples from 846 Hutterites were obtained with informed consent. Exclusion criteria included an inadequate blood sample available for all biochemical and/or genetic determinations. The study was approved by ethical review panels of the Universities of Alberta and Toronto.
Biochemical and Genetic Analyses
Sufficient DNA and
phenotypic information were obtained for
analysis from 788 Hutterites. Plasma lipids, lipoproteins, and
apolipoproteins were determined as
described.7 8 9
Genotypes of AGT codons 174 and 235, apolipoprotein
(apo) B (APOB) codons 3611 and 4154, paraoxonase
(PON) codon 192, lipoprotein lipase (LPL) intron
6, very-low-density lipoprotein receptor (VLDLR)
5'-trinucleotide repeat, APOC3
3'-untranslated region, LDL receptor-related protein
(LRP) 5'-tetranucleotide repeat, clotting
factor VII (F7) codon 353, hepatic lipase (HL)
codon 202, angiotensin-converting enzyme
(ACE) I-D polymorphism, LDL receptor (LDLR)
exon 12, and apo E (APOE) were determined as
described.9
Statistical Analysis
SAS (version 6.1) was used for all
statistical
comparisons.13 The distribution of systolic and
diastolic BPs was significantly nonnormal
in this data set. Therefore, for parametric statistical
analyses, each quantitative variable was transformed and
subjected to analysis of normality as
described.6 7 8 9 The
transformed variables were used for
parametric statistical analyses, but the nontransformed
values are presented in the tables.
ANOVA was performed by use of the general linear models procedure with stepwise inclusion to determine the sources of variation for systolic BP and diastolic BP, with F tests computed from the type III sums of squares.13 This form of sum of squares is applicable to unbalanced study designs and reports the effect of an independent variable after adjustment for all other variables included in the study model. Dependent variables were transformed systolic and diastolic BPs. Independent variables were age, log BMI, current treatment with antihypertensive agents, and colony of origin, with the latter variable included to correct for contribution to variation that was related to other shared genetic and environmental factors. Also included as independent variables were plasma concentrations of lipids and apo B– and apo A-I–containing lipoproteins. Finally, all genotypes were included as independent variables. Since we wished to identify significant genotypexsex interactions, we included interaction terms for sex with genotype that were significantly associated with BP.
When a significant association between a genetic variable and BP was identified with the ANOVA, BP differences between individuals classified by genotype were compared by use of a t test for least-squares means.13 For significant associations between continuous variables and BP identified by ANOVA, the Pearson correlation coefficient was calculated.13
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Results |
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Baseline Characteristics of the Study Sample
There were 788 subjects (45.0% of whom were men) for whom there was sufficient phenotypic and genotypic information for statistical analysis. The mean age, BMI, systolic BP, and diastolic BP in this sample were 37.5±14.5 years, 28.5±6.0 kg/m2, 126.1±14.8 mm Hg, and 80.6±9.8 mm Hg, respectively.
Allele frequencies are shown in Table
1
. As
previously reported, only the ACE I-D genotype
frequencies deviated from those predicted by the Hardy-Weinberg law in
this sample of
Hutterites.6 7 8 9
Significant linkage
disequilibrium was detected between alleles of the two
polymorphic sites in AGT, due mainly to a higher than
predicted prevalence of homozygotes for both 235M and 174T had there
been linkage equilibrium.6
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Determinants of Variation in Systolic BP
The results of the
ANOVA are shown in Table 2. One
ANOVA each was performed for systolic BP and
diastolic BP. Since ANOVA takes multiple comparisons into
account, we did not have to adjust the levels of nominal significance.
Significant associations were identified between transformed
systolic BP and the independent variables age, sex, log
BMI, treatment with antihypertensive agents, and colony of origin.
Systolic BP was significantly associated with AGT
codon 174 genotype (P=.0021) and APOB
codon 4154 genotype (P=.034) but not with any other
genetic or biochemical variable. Systolic BP was also
significantly associated with the AGT codon 174
genotypexsex interaction term (P=.0017) but not
with any other genotypexsex interaction terms. The significant
interaction term was due to the highly significant
phenotype-genotype association in men but not in
women, as we previously reported.6
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Homozygotes for the
AGT 174T allele had the lowest mean
systolic BP (Table 3), heterozygotes had an
intermediate level, and homozygotes for the AGT 174M
allele had the highest mean systolic BP. Pairwise
comparisons showed that mean systolic BP in homozygotes for the
AGT 174T allele was significantly lower than in
heterozygotes and in homozygotes for the 174M allele
(P=.0024 and P=.022, respectively). This is
consistent with an autosomal codominant effect of the
alleles of this marker on systolic BP.
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Homozygotes for the
APOB 4154K allele had the lowest
mean systolic BP (Table 3
), heterozygotes had an intermediate
level, and homozygotes for the APOB 4154E allele had the
highest mean systolic BP. Pairwise comparisons showed that mean
systolic BP in homozygotes for the APOB 4154K
allele was significantly lower than in heterozygotes and in
homozygotes for the 4154E allele (P=.020 and
P=.0093, respectively). This is consistent with an
autosomal codominant effect of the alleles of this marker on
systolic BP.
In contrast to diastolic BP, systolic BP was very significantly associated with age (P=.0007). The Pearson correlation coefficient between systolic BP and age was .31 (P<.0001).
Determinants of Variation in Diastolic BP
Significant
associations were identified between transformed
diastolic BP and the independent variables sex,
treatment with antihypertensive medications, log BMI, and colony of
origin. Diastolic BP was significantly associated with
AGT codon 174 genotype (P=.046),
APOB codon 4154 genotype (P=.026), and
F7 codon 353 genotype (P=.040) but not
with any other genetic variable or with any genotypexsex
interaction term.
Homozygotes for the AGT 174T allele had the
lowest mean
diastolic BP (Table 3), heterozygotes had an intermediate
level, and homozygotes for the AGT 174M allele had the
highest mean diastolic BP. Pairwise comparisons showed that
mean diastolic BP in homozygotes for the AGT
174T allele was significantly lower than in heterozygotes and in
homozygotes for the 174M allele, although the levels of
significance were borderline (P=.050 and
P=.055,
respectively). This is consistent with an autosomal codominant
effect of the alleles of this marker on diastolic BP,
although with a lower level of significance than for systolic
BP.
Homozygotes for the APOB 4154K allele had the highest
mean diastolic BP (Table 3), heterozygotes had the lowest
level, and
homozygotes for the APOB 4154E allele had an
intermediate mean systolic BP. Pairwise comparisons showed a
significant difference in mean diastolic BP only between
heterozygotes and homozygotes for the APOB 4154E allele
(P=.014). The significant difference in
diastolic BP for this marker was seen in comparison of the
two genotypic classes with the largest numbers of subjects. It is very
possible that, as for systolic BP, the APOB codon
4154 alleles have a codominant effect on diastolic
BP.
Homozygotes for the F7 353Q allele had the lowest mean
diastolic BP (Table 3), heterozygotes had an intermediate
level, and homozygotes for the F7 353R allele had the
highest mean diastolic BP. Pairwise comparisons showed a
significant difference in mean diastolic BP only between
heterozygotes and homozygotes for the F7 353R allele
(P=.011). The significant difference in
diastolic BP for this marker was seen in comparisons of the
two genotypic classes with the largest numbers of subjects. This is
consistent with an autosomal codominant effect of the
alleles of this marker on diastolic BP.
In contrast to systolic BP, diastolic BP was very significantly associated with concentrations of plasma apo B (P=.0004) and also concentrations of plasma triglycerides and non-HDL cholesterol (data not shown). The Pearson correlation coefficient between diastolic BP and plasma apo B was .38 (P<.0001).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The principal new finding from this study in Hutterites is the identification of associations between variation in BP and variation in candidate genes in lipoprotein metabolism and the coagulation cascade. Specifically, in a large multivariate analysis, we found new significant associations between (1) APOB codon 4154 genotype and variation in systolic BP, (2) APOB codon 4154 and variation in diastolic BP, and (3) variation in F7 codon 353 and variation in diastolic BP. We observed again the previously reported significant male-specific association between AGT codon 174 genotype and variation in BP in this study sample.6 We also found a highly significant association between plasma apo B concentration and variation in diastolic but not systolic BP. Although the associations with BP were significant, we note that the levels of significance for the APOB and F7 genes were marginal, given the relatively large sample size and number of covariates. Furthermore, the population studied had unique genetic and environmental attributes, which allowed us to detect modest associations. However, it is not obvious that these results can be generalized to suggest that these associations exist in comparably sized outbred study samples. Clearly, more studies are required.
Apo B is the sole protein component of LDL, whose plasma levels are associated with an increased risk of CHD.14 The amino acid variant at APOB codon 4154 underlies one of five classic apo B epitopes that were detected by use of autoantibodies in transfused individuals.15 Case-control studies have failed to demonstrate a consistent association between the genotype at APOB codon 4154 and plasma lipoproteins.14 We previously showed that the genotype at APOB codon 4154 was not associated with variation of plasma apo B–related traits in this sample of Hutterites.9 Therefore, the association between APOB 4154 genotype and BP in the present study was not likely to have been through plasma apo B concentrations. It is possible that variation of APOB codon 4154 may have an impact on CHD through a mechanism that is independent of plasma apo B concentrations. For example, at least six case-control studies have shown associations between the APOB codon 4154 genotype and CHD, unrelated to variation in plasma lipoprotein concentrations.14 Alternatively, it is possible that in this study sample, APOB codon 4154 genotype was in linkage disequilibrium with a structural variant within either APOB or a proximal gene on chromosome 2, which had a functional impact on BP through a different mechanism.
In addition to a concentration-independent association between apo B genotype and BP, we found a concentration-dependent positive correlation between plasma apo B–containing lipoproteins and diastolic BP but not systolic BP. The basis for such a strong, specific association between plasma apo B and diastolic BP is not clear. Plasma apo B and diastolic BP may share common determinants. For example, a fundamental defect in glucose disposal has been proposed to underlie the syndrome that includes compensatory hyperinsulinemia, elevated plasma apo B–containing lipoproteins, and hypertension.16 However, components in the metabolic pathways affecting these variables interact so closely that the mechanisms that contribute to the elevation in both apo B and BP are not easily distinguished. Hyperinsulinemia itself has been proposed to directly raise both apo B and BP.16 Alternatively, oxidation of apo B–containing lipoproteins, particularly LDL, impairs endothelium-mediated relaxation in arterial segments.17 This suggests that changes in vascular responsiveness that may predispose to hypertension may be secondary to changes in plasma lipoprotein concentrations. Furthermore, lowering of plasma cholesterol and apo B was shown to have a beneficial effect on endothelium-mediated responsiveness of the coronary arteries.18 19 However, it is not clear whether sustained high levels of apo B can chronically inhibit, or whether reduction in plasma apo B can disinhibit, vasorelaxation in peripheral arteries, with a clinical impact on diastolic BP.
Furthermore, we observed in this study sample a significant positive correlation between age and systolic BP but not diastolic BP. Such an association is consistent with the concept that aging-related factors, such as arterial vessel wall stiffness or related physical properties, may be more related to systolic BP than to diastolic BP. In contrast, factors related to intermediary metabolism, such as plasma apo B–containing lipoproteins, may be more closely related to diastolic BP than to systolic BP.
Finally, we observed an association between diastolic BP and the genotype of F7 codon 353. Factor VII is the first enzyme involved in the extrinsic pathway of blood coagulation.20 Factor VII coagulant activity has been prospectively associated with the risk of future fatal coronary events in men.21 Genotypic variation at F7 codon 353 has been shown to account for substantial variation in plasma factor VII mass and activity.22 There is also evidence that there is a genotype-specific difference in the association between plasma triglycerides and factor VII activity.23 The presence of the F7 allele with Gln at residue 353 is associated with fewer active factor VII molecules and about 20% reduction of plasma factor VII coagulant activity.22 23 Diastolic BP was significantly lower in our subjects who carried the F7 allele with Gln at residue 353. Thus, it may be possible that a lower plasma factor VII mass and/or activity may have either a direct or an indirect effect on plasma vascular tone independent of activity within the coagulation cascade. For example, formation of the factor VII/tissue factor complex primarily stimulates coagulation, but there may also be some non–thrombosis-related activity of either factor VII or tissue factor that may affect vascular tone. Alternatively, it is also possible that in this sample of Hutterites, the F7 codon 353 genotype was in linkage disequilibrium with another structural variant within either F7 or a proximal gene on chromosome 15, which had a functional impact on BP through a different mechanism.
We sought to control for a possible pleiotropic effect of obesity both on BP and on plasma concentrations of apo B–containing lipoproteins by including BMI as a covariate in all analyses. However, the mean BMI in our study sample was almost 29 kg/m2, and more than 50% of subjects had a BMI exceeding 27 kg/m2. Therefore, the phenotype-genotype associations that we detected occurred against a background of a remarkably heavy study sample. Although variation in BMI was highly significantly associated with variation in both systolic and diastolic BPs, it remains possible that the association of BP with the genotypes depended on a background of very high BMI.
In summary, we observed that genetic variations in AGT, APOB, and F7 were associated with interindividual variation in both systolic and diastolic BPs in a genetic isolate. In addition to age of onset, sex, and race, hypertension has been associated with insulin resistance,24 plasma renin activity,25 sodium sensitivity,26 sensitivity to angiotensin II,26 urinary kallikrein secretion,27 calcium metabolism,28 hyperlipidemia,29 and coagulation abnormalities.30 Studying candidate genes whose products act in these pathways in highly related subjects will further help apportion the relative contribution of genetic factors to BP. Newer analytical approaches31 32 could further help to identify new genes that are important in polygenic diseases, like hypertension, and help to identify high-risk individuals who are candidates for interventions.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the Medical Research Council of Canada, the National Health Research and Development Program of Canada, and the Heart and Stroke Foundations of Ontario and Canada. Dr Hegele is a Career Investigator of the Heart and Stroke Foundation of Canada. We would like to thank Stanley Chan (APOB codon 3611 genotypes), Kevin Higgins (APOB codon 4154 genotypes), Greg Ip (APOE and LPL genotypes), Ulana Kawun (F7 genotypes), Dennis Lam (LDLR and VLDLR genotypes), Edwin Lee (AGT and PON genotypes), Patricia Ram (AGT and HL genotypes), Stefan Sadikian (LRP and ACE genotypes), and Tammy Znajda (APOC3 genotypes) for their technical assistance. Teresa Lippingwell and Liling Tu archived the phenotypic and genotypic data. Dr Adele Csima, Department of Biostatistics, University of Toronto, provided expert advice regarding our statistical analyses.
Received October 31, 1995; first decision November 14, 1995; accepted November 14, 1995.
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