Earlier studies have demonstrated the interaction between ADD1 and ACE in relation to arterial properties. We investigated whether arterial characteristics might also be related to interactions of ADD1 with other renin–angiotensin system genes. Using a family-based sampling frame, we randomly recruited 1064 Flemish subjects (mean age, 43.6 years; 50.4% women). By means of a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries. In multivariate-adjusted analyses, we assessed the multiple gene effects of ADD1 (Gly460Trp), AGT (C–532T and G–6A) and AT1R (A1166C). In ADD1 Trp allele carriers, but not in ADD1 GlyGly homozygotes (P-value for interaction ⩽0.014), femoral cross-sectional compliance was significantly higher (0.74 vs 0.65 mm2 kPa−1; P=0.020) in carriers of the AT1R C allele than in AT1R AA homozygotes, with a similar trend for femoral distensibility (11.3 vs 10.2 × 10−3 kPa−1; P=0.055). These associations were independent of potential confounding factors, including age. Family-based analyses confirmed these results. Brachial diameter (4.35 vs 4.18 mm) and plasma renin activity (PRA) (0.23 vs 0.14 ng ml−1 h−1) were increased (P⩽0.005) in AGT CG haplotype homozygotes compared with non-carriers, whereas the opposite was true for brachial distensibility (12.4 vs 14.4 × 10−3 kPa−1; P=0.011). There was no interaction between AGT and any other gene in relation to the measured phenotypes. ADD1 and AT1R interactively determine the elastic properties of the femoral artery. There is a single-gene effect of the AGT promoter haplotypes on brachial properties and PRA.
Adducin is a ubiquitously expressed membrane skeleton protein that consists either of α- and β- or α- and γ-subunits. Mutation of the α-adducin gene (ADD1) entails increased Na+,K+-ATPase activity1, 2 and increased renal tubular sodium reabsorption.3 Variation in the Na+,K+-ATPase activity and in the intracellular Na+ concentration might influence the sodium-dependent transmembranous Ca+2 transport in vascular smooth muscle cells.4
We have earlier demonstrated that interaction between the ADD1 Gly460Trp and the angiotensin-converting enzyme ACE I/D polymorphisms modulates femoral artery properties. Indeed, in the presence of the ADD1 460Trp allele, femoral intima-media thickness was higher in ACE D carriers than in II homozygotes.5 Moreover, in ACE DD homozygotes, carriers of mutated ADD1 had higher femoral distensibility and cross-sectional compliance than those with the wild-type ADD1.6 In the prospective Flemish Study on Environment, Genes and Health Outcomes, the combination of ACE DD homozygosity and mutated ADD1 worsened cardiovascular prognosis to a similar extent as classical risk factors.7 Experimental studies in fibroblasts from 51 subjects and in transfected cell models showed higher membrane-bound ACE activity in cells carrying the ADD1 Trp allele.7
In view of the aforementioned evidence,1, 2, 3, 4, 5, 6, 7 we hypothesized that arterial properties might be related not only to interactions of ADD1 with ACE, but also to interactions of ADD1 with other genes encoding various components of the renin–angiotensin system. We therefore genotyped Flemish Study on Environment, Genes and Health Outcomes participants for the angiotensinogen (AGT) C–532T and G–6A promoter polymorphisms as well as for the intronic A1166C polymorphism in the angiotensin II type-1 receptor gene (AT1R).
Materials and methods
The Flemish Study on Environment, Genes and Health Outcomes is part of the European Project on Genes in Hypertension8 and is embedded in the InGenious HyperCare Network of Excellence. From August 1985 until July 2003, we recruited a random sample of families from a geographically defined area in Northern Belgium. The Ethics Committee of the University of Leuven approved the study. All participants or their parents gave informed written consent. The participation rate averaged 64.3%.
Of 1306 participants who underwent a vascular ultrasound examination,9 1180 (90.3%) had high-quality images obtained at the common carotid, femoral and brachial arteries. We excluded 80 participants, because of missing genotypes, and 26 because of incomplete information on important covariates. In addition, we detected 10 cases of inconsistency in Mendelian segregation. Thus, the number of subjects analysed totaled 1064.
Clinical and biochemical measurements
For at least 3 h before the examination, the participants refrained from heavy exercise, smoking, alcohol and caffeine-containing beverages. Trained nurses measured the subjects' anthropometric characteristics, heart rate and blood pressure. They administered a questionnaire to collect information about each participant's recent medical history, smoking and drinking habits, and intake of medications. Each subject's blood pressure was the average of five consecutive readings measured before the ultrasound examination after the subjects had rested in the sitting position for at least 5 min. Pulse pressure was systolic minus diastolic blood pressure. Mean arterial pressure was diastolic pressure plus one-third of pulse pressure. Hypertension was a blood pressure of at least 140 mm Hg systolic or 90 mm Hg diastolic, and/or the use of antihypertensive drugs. Body mass index was weight in kilograms divided by the square of height in metres. On the day of the vascular measurements, venous blood samples were drawn to measure the blood glucose concentration and plasma renin activity (PRA). The participants also collected an exactly timed urine sample over 4–6 h to measure the excretion of sodium and aldosterone.10 Diabetes mellitus was a self-reported diagnosis, use of antidiabetic medication or a fasting or casual blood glucose concentration ⩾7.0 mmol l−1 (126 mg per 100 ml) or ⩾11.1 mmol l−1 (200 mg per 100 ml), respectively.11 Hypercholesterolaemia was a serum level of total cholesterol ⩾5.16 mmol l−1 (200 mg per 100 ml) or treatment with lipid-lowering drugs.12 We determined PRA (RIA-0180; DRG Instruments GmbH, Marburg an der Lahn, Germany) and the urinary aldosterone concentration (DSL-8600 Active; Diagnostic Systems Laboratories Inc., Webster, TX, USA) by radioimmunoassay, according to the instructions provided by the manufacturers of the analytic kits.
By means of a pulsed ultrasound wall-tracking system (Wall Track System; Pie Medical, Maastricht, The Netherlands), three trained researchers obtained vascular measurements at the common carotid artery 2 cm proximal of the carotid bulb, at the femoral artery 1 cm proximal of the bifurcation into the profound and superficial branches, and at the right brachial artery 2 cm proximal of the antecubital fossa.
During the ultrasound examination, an automated oscillometric device (Dinamap 845; Critikon Inc., Tampa, FL, USA) recorded blood pressure at the upper arm at 5-min intervals. As for the conventional auscultatory measurements, cuff size was adjusted to the circumference of the upper arm.8 Standard cuffs had an inflatable bladder of 12 × 24 cm. Larger cuffs had a 15 × 35 cm bladder. As described elsewhere,13 the observers used applanation tonometry with a pencil-shaped probe (Millar Instruments Inc., Houston, TX, USA) and calibration to mean arterial pressure and diastolic blood pressure at the brachial artery to derive the local pulse pressure at the other arteries. We computed the distensibility (DC) and cross-sectional compliance (CC) from the diastolic cross-sectional area (A), the systolic increase in cross-sectional area (ΔA) and the local pulse pressure (PP):14 DC=(ΔA/A)/PP and CC=ΔA/PP. A and ΔA were calculated from the diameter (D) and the change in diameter (ΔD) as A=π × (D/2)2 and ΔA=π × [(D+ΔD)/2)2−π × (D/2)2], respectively. The intraobserver intrasession variability was below 10% for the carotid measurements, below 5% for the femoral and brachial diameter, and amounted from 10 to 15% for the femoral and brachial cross-sectional compliance and distensibility.15 The intraobserver intersession and interobserver intrasession variability were of the same order of magnitude.15
We extracted DNA from white blood cells. For genotyping, we used a 5′ nuclease detection assay implemented on an ABI Prism 7700 Sequence Detection System (Applied Biosystems Inc., Foster City, CA, USA). Primers, probes and PCR conditions for ADD1 Gly460Trp (rs4961 dbSNP),16 AT1R C1166A17 and AGT A–532C and G–6A17 genotyping have already been described in detail elsewhere.
For database management and statistical analyses, we used SAS software (SAS Institute, Cary, NC, USA), version 9.1. We normalized the distributions of PRA and of the urinary excretion rates of sodium and aldosterone by a logarithmic transformation. We compared means and proportions, using the large sample z-test and Fisher's exact test, respectively. Our statistical methods also included single and multiple linear regressions. We searched for possible covariates of the arterial phenotypes, using a stepwise regression procedure with the P-values for independent variables to enter and to stay in the model set at 0.15. As covariates, we considered observer, sex, age, body mass index, heart rate, mean arterial pressure and design variables (0, 1), coding for current smoking, alcohol intake and use of antihypertensive drugs.
We tested linkage disequilibrium and we reconstructed haplotypes, using the SAS procedures PROC ALLELE and PROC HAPLOTYPE, as implemented in the genetics module of the SAS software. In our analyses, we included only those AGT haplotypes that were unambiguously determined.
In a population-based approach, we applied a generalization of the standard linear model as implemented in the PROC MIXED procedure of the SAS package to test the associations between phenotypes and single-nucleotide polymorphisms or haplotypes, while accounting for the nonindependence of phenotypes within families and adjusting for covariates. We tested the interactions between genotypes and between genotypes and anthropometric characteristics by introducing the appropriate interaction terms into the models.
Furthermore, in the family-based analyses, we performed a transmission disequilibrium test for quantitative traits (QTDT). We evaluated the within-family and between-family components of phenotypic variance, using the orthogonal model as implemented by Abecasis et al.18 in the QTDT software, version 2.4, available at http://www.sph.umich.edu/csg/abecasis/QTDT. The within-family component of phenotypic variance is robust to population stratification.
Characteristics of participants
We divided study participants into founders (n=152) and unrelated subjects (n=252) as compared with the offsprings (n=660). Subjects in the founders group (mean age 51.0 years; range 11.8–81.8 years) were older than offspring (39.1 years; range 10.9–81.0 years). Table 1 summarizes their demographic characteristics. The study sample included 315 hypertensive patients (29.6%). Of 134 (12.6% of total study population) treated hypertensive patients, 53 (39.6%) were on monotherapy and 81 (60.4%) were taking different classes of antihypertensive drugs. Antihypertensive therapy included β-blockers in 80 (59.7%) patients, diuretics in 44 (32.8%), calcium-channel blockers in 28 (20.9%), angiotensin-converting enzyme inhibitors in 14 (10.4%), centrally acting drugs in 4 (3.0%) and α-blockers in 2 (1.5%) patients. The study sample included 580 (54.5%) patients with hypercholesterolaemia, of whom 15 (2.6%) were receiving lipid-lowering treatment. Offsprings reported alcohol intake more frequently than founders (52.6 vs 30.7%). For smoking, the corresponding frequencies were 29.2 and 30.2%, respectively. In smokers, median tobacco use was 14 cigarettes per day (interquartile range, 8–20). In drinkers, the median alcohol consumption was 10 g day−1 (interquartile range, 4–20).
Table 2 lists the arterial properties by generation and vascular territory. Local pulse pressure at the three arteries under study was similar (0.31<P<0.97) in founders and offsprings. Carotid and femoral distensibility and cross-sectional compliance and brachial diameter were lower in founders than in offsprings. The opposite was true for brachial distensibility and cross-sectional compliance and carotid diameter.
Genotype and haplotype frequencies
Genotype frequencies (Table 3) complied with Hardy–Weinberg proportions in the founder generation (0.08<P<0.62). The two polymorphisms in the AGT promoter were in significant linkage disequilibrium (Lewontin's D=0.93; P<0.0001). In 10 subjects, we could not reliably reconstruct the haplotypes. The haplotype frequencies were 56.3% for the combination of –532C and –6G (H1-CG), 33.3% for the combination of –532C and –6A (H2-CA) and 10.4% for the combination of –532T and –6A (H3-TA).
Population-based study of genotypes
In stepwise multiple regression analyses, in line with our previous publications,9 we identified the following covariates as significant determinants of one or more of the arterial phenotypes in the three vascular beds under study: sex, age, body mass index, mean arterial pressure, heart rate, serum total cholesterol, smoking, daily alcohol intake in excess of 5 g and use of antihypertensive drugs (Table 4). We adjusted all phenotype–genotype associations involving arterial properties for these covariates, and in addition for observer.
In single-gene analyses, involving all subjects, none of the multivariate-adjusted phenotype–genotype associations reached statistical significance with the exception of brachial artery diameter in relation to the AT1R polymorphism. C allele carriers had a slightly larger brachial diameter compared with AA homozygotes (4.39±0.03 vs 4.29±0.03 mm; P=0.016).
In multivariate-adjusted multiple-gene analyses (Table 5), we found significant interaction between ADD1 and AT1R in relation to femoral cross-sectional compliance (P=0.014) and femoral distensibility (P=0.023). In ADD1 Trp allele carriers, but not in ADD1 GlyGly homozygotes, femoral cross-sectional compliance was significantly higher (P=0.020) in carriers of the AT1R C allele than in AT1R AA homozygotes, with a similar trend for femoral distensibility (P=0.055).
In sensitivity analyses, we narrowed the age range first by excluding 85 participants younger than 20 years and next by only including in our analyses subjects with an age range corresponding to the 10th to 90th percentile interval (20–70 years; n=931) or to the interquartile range (34–55 years; n=533). As shown in Table 5, the results of these sensitivity analyses were confirmatory. Similarly, when we repeated the sensitivity analyses excluding 142 treated patients on antihypertensive (n=134) or lipid-lowering (n=15) drugs, we also obtained consistent results (Table 6). The genotype-by-age interactions in the whole study population were also not significant (P⩾0.24).
Population-based study of haplotypes
Brachial diameter was significantly larger (Figure 1) in H1-CG homozygotes compared with non-carriers of this haplotype (4.35±0.04 vs 4.18±0.05 mm; P=0.004). Furthermore, brachial distensibility was lower in H1-CG homozygotes than in those subjects not carrying this haplotype (12.4±0.6 vs 14.4±0.7 × 10−3 kPa−1; P=0.011). The number of copies of the AGT H1-CG haplotype had an additive effect, as exemplified by the P-values for linear trend (Figure 1). The aforementioned associations with brachial diameter and distensibility were consistent irrespective of sex (P⩾0.40), age (P⩾0.75) and sodium excretion rate (P⩾0.26). We did not find any association of the properties of the carotid or femoral arteries with the AGT haplotypes (0.22⩽P⩽0.74). There were also no gene–gene interactions between the AGT haplotypes and the ADD1 (P⩾0.11) or AT1R (P⩾0.20) polymorphisms in relation to any of the arterial phenotypes in the three arterial beds.
In the analysis adjusted for sex, age, body mass index, mean arterial pressure, heart rate and use of antihypertensive treatment, PRA was significantly higher in H1-CG homozygotes than in subjects not carrying this haplotype (0.23 ng ml−1 h−1 (95% confidence interval (CI), 0.18–0.30 ng ml−1 h−1) vs 0.14 ng ml−1 h−1 (95% CI, 0.12–0.16 ng ml−1 h−1); P=0.005; Figure 1). These findings remained consistent after exclusion of 134 subjects on antihypertensive treatment (data not shown).
Family-based study of genotypes
Our study sample consisted of 58 pedigrees, of which 25 spanned more than two generations and additionally of 252 unrelated subjects. The number of offsprings per pedigree was less than 3 in 24 pedigrees, ranged from three to eight in 30 families and amounted to more than eight in four pedigrees.
The multivariate-adjusted heritability estimates, as reported by Abecasis' software, were 0.31 for the femoral distensibility and 0.43 for the femoral cross-sectional compliance (P<0.001 for both). Abecasis' orthogonal model did not reveal population stratification (0.11⩽P⩽0.97). In 115 informative offsprings, carrying the ADD1 Trp allele, transmission of the mutated ATR1 C allele was associated with a significant increase in femoral distensibility (+2.46±1.06−3 kPa−1; χ2=5.39; P=0.022) with a similar trend in femoral cross-sectional compliance (+0.12±0.07 mm2 kPa−1; χ2=2.63; P=0.11). In 184 informative ADD1 GlyGly homozygotes, these effect sizes were −0.19±0.85 × 10−3 kPa−1 (χ2=0.05; P=0.82) and +0.01±0.06 mm2 kPa−1 (χ2=0.05; P=0.82), respectively.
Family-based association study of AGT haplotypes
The multivariate-adjusted heritability estimates, as reported by Abecasis' software, were 0.52 for the brachial diameter, 0.38 for brachial distensibility and 0.45 for PRA (P<0.001 for all). Abecasis' orthogonal model did not reveal population stratification (0.06⩽P⩽0.81). In 300 informative offsprings, the orthogonal model did not show significant association of transmission of H1-CG with brachial diameter (+0.07±0.06 mm; χ2=1.33; P=0.25), brachial distensibility (–0.55±0.76 × 10−3 kPa−1; χ2=0.53; P=0.46) or PRA (0.91 ng ml−1 h−1 [95% CI, 0.63–1.31 ng ml−1 h−1]; χ2=0.26; P=0.61).
Our current study builds on earlier findings showing interactions among the ADD1, ACE and aldosterone synthase genes in relation to femoral intima-media thickness5 and carotid and femoral distensibility.6 We assessed whether the properties of the large arteries might also be related to interactions of ADD1 with other genes of the renin–angiotensin system. The key finding of our study was that femoral cross-sectional compliance and distensibility were higher in AT1R C allele carriers than in AT1R AA homozygotes, but that this association was only observed in the presence of the mutated ADD1 Trp allele, and not in ADD1 GlyGly homozygotes. In the family-based analyses, we did not find any evidence for population stratification. Transmission of the AT1R C allele was associated with higher femoral distensibility in an offspring carrying the mutated ADD1 Trp allele. Furthermore, single-gene analyses showed increased brachial diameter associated with the AT1R C allele and larger brachial diameter and lower brachial distensibility associated with the AGT H1-CG haplotype homozygotes. The latter association was not modified by interaction with the other genes under study.
Epidemiological findings only allow speculation about the plausibility of the observed associations and possible underlying mechanisms. In tissue extracted from 68 term placentas of European British ancestry, Abdollahi et al.19 demonstrated that allele and mRNA haplotypes carrying AT1R 1166C exhibited lower expression of angiotensin II type-1 receptor mRNA. If these findings can be extrapolated to the brachial artery, they might explain the larger diameter, because of the lower sensitivity to the vasoconstrictive effects of angiotensin II.
Substitution of glycine with tryptophane in the α-subunit of the adducin cytoskeleton protein leads to higher activity of Na+,-K+-ATPase1, 2 and increased tubular sodium reabsorption in the kidney.3 Higher body sodium suppresses the generation of angiotensin II. Combined with a lower expression of the AT1R in AT1R C allele carriers,19 this might explain the interaction between the two genes in relation to femoral cross-sectional compliance and distensibility. Alternatively, it is also conceivable that the constitutive activation of the sodium pump in ADD1 Trp allele carriers not only occurs in renal tubular cells, but that it might also be present in vascular smooth muscle cells.4 Mutation of ADD1 by decreasing intracellular sodium could enhance sarcolemmal Na+/Ca2+ exchange and, through calcium-dependent pathways, decrease excitation–contraction coupling,20 and hence increase the distensibility and cross-sectional compliance of muscular arteries, such as the femoral artery.
The AGT G–6A variant represents a guanine-to-adenine substitution 6 bp upstream from the initiation site of transcription. This nucleotide substitution is associated with a slightly higher basal rate of AGT gene transcription, which could account for the increase in plasma AGT in carriers of the –6A allele.21 Studies involving healthy subjects or French families also showed higher plasma AGT levels in carriers of the AGT –532T allele.17, 22 As the –532 site is located within a consensus sequence of the AGT gene-binding transcription factor AP-2, the C–532T polymorphism might also modulate AGT gene transcription.17 In our study, the C–532T and G–6A polymorphisms of the AGT gene were in linkage disequilibrium. This finding is in keeping with other published data on the haplotype structure of the AGT gene.22, 23 Thus, carriers of H2-CA or H3-TA might have an elevated AGT concentration in both plasma and tissues. Our finding that H2-CA or H3-TA carriers had lower PRA is in line with this hypothesis. In subjects with a suppressed renin–angiotensin system and lower circulating volume, the diameter of the brachial artery might be smaller, and hence brachial distensibility might be higher.24
In keeping with our previous study,5 we did not find any association between the polymorphisms under study and the properties of the elastic carotid artery. The central elastic arteries, such as the carotid artery, and the more peripheral muscular conduit vessels, including the brachial and femoral arteries, have different properties.25 Going from the central to the peripheral arteries, the collagen/elastin ratio reverses, vascular smooth muscle cells become the predominant component of the arterial wall and the phenotype of the vascular smooth muscle cells changes.25 Thus, the effects of genetic variations in ADD1 and the renin–angiotensin system genes on arteries must be complex and may depend on the vessel wall component that is involved.6
Our study should be interpreted within the context of its limitations. First, our epidemiological study demonstrated association of arterial properties with variation in ADD1 and various genes of the renin–angiotensin system, but did not provide direct information on the mechanisms underlying these phenotype–genotype associations. Second, arterial measurements are quantitative traits prone to measurement error. However, the repeatability and reproducibility of the arterial phenotypes collected in this study were high.15 Moreover, we adjusted for observer bias. For the interaction between the ADD1 and AT1R genes, there was consistency between the population-based and the family-based analyses. We did not find any evidence for population stratification. Third, in contrast to the most recent guidelines from the European Societies of Hypertension and Cardiology,26 we based mean arterial pressure and the diagnosis of hypertension only on office blood pressure measurement without confirmation by 24-h ambulatory monitoring. Moreover, arterial phenotyping took place before the 2007 European Societies of Hypertension and Cardiology guidelines26 were issued.
In conclusion, ADD1 and AT1R interactively determine the elastic properties of the femoral artery. The underlying mechanisms remain to be elucidated. There is a single-gene effect of the AGT promoter haplotypes on brachial properties, which might be mediated by different circulating levels of angiotensinogen and angiotensin II as suggested by lower PRA in H1-CG haplotype homozygotes.
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This study would not have been possible without the voluntary collaboration of the participants. The municipality Hechtel-Eksel provided logistic support. We acknowledge the expert technical assistance of Sandra Covens, Linda Custers, Marie-Jeanne Jehoul, Hanne Truyens and Ya Zhu (Studies Coordinating Centre, Leuven, Belgium). The European Project on Genes in Hypertension (EPOGH) is endorsed by the European Council for Cardiovascular Research and the European Society of Hypertension. Research included in this report was supported by the European Union (grants IC15-CT98-0329-EPOGH, LSMH-CT-2006-037093 InGenious HyperCare and HEALTH-F4-2007-201550 HyperGenes); the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0424.03, G.02.56.05 and G.0575.06); the Katholieke Universiteit Leuven, Belgium (OT/00/25 and OT/05/49); the Czech Society of Hypertension; the Ministero Universitá e Ricerca Scientifica of Italy (PRIN Grant 2006065339_01); and the Else Kröner-Fresenius Stiftung (P27/05//A24/05//F01). EB is supported by a Heisenberg Professorship from the Deutsche Forschungsgemeinschaft (Br 1589/8-1).
Conflict of interest
About this article
- arterial stiffness
- arterial distensibility
- angiotensin II type 1 receptor
- clinical genetics
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