The Lys198Asn Polymorphism in the Endothelin-1 Gene Is Associated With Blood Pressure in Overweight People
Abstract
Abstract—There is accumulating evidence that endothelin-1 plays an important role in vascular pathophysiology. Our objective was to examine whether molecular variations at the endothelin-1 locus were involved in susceptibility to myocardial infarction and variation in blood pressure. The entire coding sequence and 1.4 kb of the 5′ flanking region were screened. Five polymorphisms were detected, which were genotyped in the ECTIM (Etude Cas-Témoin de l’Infarctus du Myocarde) Study, a multicenter study comparing 648 male patients who had survived a myocardial infarction and 760 population-based controls. The polymorphisms were not associated with myocardial infarction, nor did they contribute to blood pressure levels in the population at large. However, a G/T polymorphism predicting an Lys/Asn change (ET1/C198) strongly interacted (P<0.001) with body mass index in the determination of blood pressure levels. There was a steeper increase of blood pressure with body mass index in carriers of the T allele than in GG homozygotes. As a consequence, the T allele was associated with an increase of blood pressure in overweight subjects (body mass index ≥26 kg/m2), while no significant effect was observed in lean subjects (body mass index <26 kg/m2). To determine whether this finding could be replicated, the ET1/C198 was genotyped in the Glasgow Heart Scan Study, a population-based study including 619 men and 663 women. Subjects homozygous for the T allele had higher resting blood pressure levels than others (P<0.05). A similar interaction between the T allele and body mass index was observed on the maximum blood pressure achieved during a treadmill exercise test (P<0.001). In conclusion, results from 2 independent studies suggest that the ET1/C198 polymorphism is associated with blood pressure levels in overweight people.
Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced by endothelial and smooth muscle cells.1 It is found in a variety of tissues, where it acts as a modulator of vasomotor tone, cell proliferation, and hormone production (see References 2 and 323 for reviews). There is accumulating evidence from experimental and clinical data that ET-1 plays an important role in the pathophysiology of the vascular system.3 ET-1 expression is enhanced in atherosclerosis and coronary endothelial dysfunction456 and may contribute to the rupture of active atherosclerotic plaques, leading to acute ischemic events.78 Raised circulating concentrations of ET-1 have been observed in the acute phase of myocardial infarction (MI)91011 and were related to an unfavorable prognosis after MI.12 Congestive heart failure is also commonly associated with high ET-1 concentrations,131415 and long-term treatment with an endothelin-receptor antagonist has been reported to improve the survival of rats with chronic heart failure.16 Because of its vasoconstrictor and hypertrophic actions, ET-1 is also suspected of playing a role in the hypertensive process, although this is controversial.171819 In particular, plasma ET-1 concentrations are either normal or only slightly elevated in hypertensive patients.202122232425 However, concentrations found in the circulation may not reflect vascular production of ET-1, which is mostly abluminal. An overexpression of the ETA receptor and the ET-1 genes has been observed in arteries of hypertensive patients,2526 a phenomenon that could contribute to the pathogenesis of hypertension by inducing vascular wall hypertrophy. Finally, a strong argument in favor of a role of ET-1 in hypertension is that long-term treatment by an endothelin-receptor antagonist in hypertensive patients results in a significant reduction in blood pressure (BP).27
Because of the role of ET-1 in vascular pathophysiology, the gene coding for ET-1 is an obvious candidate gene for coronary heart disease and hypertension. In the present study we examined whether molecular variations at the ET-1 locus might be involved in the predisposition to MI and the determination of BP levels. For this purpose, we screened the entire coding sequence and part of the 5′ flanking region of the ET-1 gene. Among the 5 identified polymorphisms, 1 resulted in an Lys/Asn amino acid change at codon 198 (ET1/C198) and was shown to strongly interact with body mass index (BMI) in determining BP levels in 2 independent population-based studies.
Methods
The ECTIM Study
The ECTIM (Etude Cas-Témoin sur l’Infarctus du Myocarde) Study has been described previously.28 Patients with MI aged 25 to 64 years (n=648) were recruited from 4 World Health Organization MONICA (MONItoring in CArdiovascular diseases) registers in Belfast (Northern Ireland), Lille, Strasbourg, and Toulouse (France). In each region, population-based control groups (n=760) were randomly sampled from the populations covered by the registers. Informed consent was obtained from all subjects. BP was measured twice with a random-zero sphygmomanometer by trained physicians or nurses using the standardized protocol of the MONICA Project.29 The mean value of the 2 measurements was used in the analysis.
The Glasgow Heart Scan Study
The Glasgow Heart Scan Study has been described previously.30 The sample included 619 men and 663 women aged 25 to 74 years randomly selected from North Glasgow, UK, who had participated in the Third Glasgow MONICA risk factor survey in 1992. Each subject gave informed consent for the study. BP was measured twice with the MONICA protocol,29 and the mean of the 2 readings was used. A large fraction of subjects performed a treadmill exercise test. Subjects exerted to a symptom-limited maximum. The maximum heart rate and systolic BP were recorded. Subjects taking cardiovascular medications were excluded from the analysis of the treadmill exercise test because of possible modifications of the response to exercise, leaving 418 men (67.5% of the initial sample) and 455 women (68.6%) for this analysis.
Identification of Polymorphisms of the ET-1 Gene and Genotyping
The molecular screening of the ET-1 gene was performed by comparing 40 chromosomes from 20 unrelated patients with MI. DNA sequence variations were identified by polymerase chain reaction/single strand conformation polymorphism followed by sequencing, as described.31 Polymorphisms were then genotyped in all participants of the ECTIM Study. All information needed for genotyping can be found at our Internet site http://ifr69.vjf.inserm.fr/∼canvas/gene.idc-gene=EDN1.htm.
Statistical Analysis
Statistical analysis was performed with SAS statistical software (SAS Institute Inc). Comparison of genotype distributions between ECTIM cases and controls was performed by χ2 analysis. In the population-based control samples of the ECTIM Study and the Glasgow Heart Scan Study, association of BP levels with genotype was tested by ANOVA adjusted for age and population (or gender). Interaction between BMI and genotype on BP levels was tested by introducing a product term BMI×genotype in the model (test of homogeneity of slopes). Homogeneity of the interaction according to population (or gender) was tested by introducing a third-order product term in the model. Because of the relatively small number of subjects with the TT genotype, heterozygotes and homozygotes for the T allele were pooled in these analyses. Subjects on current hypertensive treatment were not excluded from analysis, but consistency of the results was checked after exclusion of these subjects. In the Glasgow Heart Scan Study, the maximum BP achieved during treadmill exercise testing was further adjusted for duration of exercise. P<0.05 was considered statistically significant.
Results
Identification of Polymorphisms
ET-1 is a 21–amino acid peptide derived from a 212–amino acid precursor, preproET-1. The ET-1 gene spans 5.5 kb on chromosome 6 and contains 5 exons and 4 introns.3233 The sequence encoding the mature ET-1 peptide is found in exon 2. Exon 1 contains the 5′-untranslated region, and exon 5 contains a portion of the 3′-untranslated region. The 5 exons, their flanking intronic regions, and 1380 bp upstream from the start of transcription were screened for sequence variation. Five polymorphisms were detected: (1) a T/G transversion at position −1370 from the start of transcription; (2) an A insertion (I)/deletion (D) in exon 1 at position +138, which has already been reported34 ; (3) a G/A transition in intron 1 at position +1932; (4) a T/C transition in intron 2 at position +3539; and (5) a G/T transversion at position +5665 affecting the 61st nucleotide of exon 5, which predicts an Lys/Asn change at codon 198 (ET1/C198).
The ECTIM Study
The 5 polymorphisms were genotyped in the ECTIM Study. Allele frequencies and pairwise linkage disequilibrium coefficients in the control populations can be found by consulting our Internet site. The genotype and allele frequencies did not differ between cases and controls for any of the polymorphisms considered.
In the population-based control samples, none of the polymorphisms displayed a significant association with BP levels by univariate analysis (data not shown). However, the ET1/C198 polymorphism strongly interacted with BMI in the determination of both systolic (SBP) and diastolic blood pressures (DBP). Characteristics of control subjects according to the ET1/C198 genotype are given in Table 1. The frequency of the ET1/C198 T allele was 0.26 in Belfast, 0.24 in Lille, 0.20 in Strasbourg, and 0.22 in Toulouse (P=0.15 for the difference between centers). The interaction between genotype and BMI reflected a steeper increase in BP levels with BMI in subjects carrying the T allele than in GG homozygotes (test of homogeneity of slopes: P<0.001 for both SBP and DBP). The interaction was observed in all 4 populations (test of the third-order interaction: P=0.54 for SBP and P=0.66 for DBP). The regression slopes of SBP levels on BMI according to ET1/C198 genotype are shown in Figure 1.
The age- and population-adjusted correlation coefficients between SBP (DBP) and BMI were 0.15 (0.15) in GG homozygotes and 0.36 (0.38) in T+ carriers. In all 4 populations, the correlations between BP levels and BMI were approximately twice as high in carriers of the T allele than in GG homozygotes (not shown). The interaction between genotype and BMI on BP remained significant even after subjects on current antihypertensive treatment were excluded.
As a consequence of this interaction, the effect of the T allele on SBP levels appeared reversed between lower and higher BMI values (Figure 1). In subjects with a BMI <26 kg/m2 (the median of BMI in the control sample), the age- and population-adjusted mean SBP levels were 129.1±1.3 in GG homozygotes and 126.2±1.5 mm Hg in T+ carriers (P=0.15). In subjects with a BMI ≥26 kg/m2, these mean levels were 135.1±1.3 and 140.4±1.5 mm Hg, respectively (P=0.009). Similar differences were observed for mean DBP levels.
The Glasgow Heart Scan Study
To determine whether the findings observed in the ECTIM Study could be replicated in an independent study, the ET1/C198 polymorphism was genotyped in the Glasgow Heart Scan Study. This large cross-sectional study, as well as the ECTIM Study, was based on samples randomly selected from a geographic area covered by a MONICA register, and resting BP was measured according to the same MONICA protocol. The mean age of participants was slightly lower than in the ECTIM Study (Table 2). The T allele frequency was estimated as 0.24 in the whole population, a figure close to those observed in the 4 ECTIM population–based samples.
In contrast to the ECTIM Study, resting BP levels significantly differed between ET1/C198 genotypes in the population as a whole, the difference mainly reflecting an increase in TT homozygotes (Table 2). This effect was consistently observed in men and women. However, unlike the ECTIM study, there was no significant interaction between BMI and genotype on resting BP levels in either gender.
In the Glasgow Heart Scan Study, a large fraction of subjects (68.1%) performed a treadmill exercise test. Subjects included in this subsample were younger (47.5 versus 58.8 years; P<0.001) and leaner (25.5 versus 28.1 kg/m2) than those who were not, but the 2 groups did not significantly differ with respect to the distribution of the ET1/C198 genotypes (P=0.47).
The mean duration of exercise and the maximum heart rate did not differ between genotypes in either gender (Table 3). By contrast, the maximum BP achieved during exercise was significantly higher in homozygotes for the T allele, with heterozygotes having intermediate levels (Table 3). The difference remained significant even after adjustment for baseline BP. Moreover, there was a significant interaction between BMI and the ET1/C198 polymorphism on maximum BP (P<0.001). Again, this interaction reflected a steeper increase of maximum BP with BMI in carriers of the T allele than in GG homozygotes (Figure 2). This interaction was observed in both genders (test of the third-order interaction: P=0.36).
In subjects with a BMI <26 kg/m2 (the approximate median of BMI in both genders), the mean maximum BP levels adjusted for age, gender, and duration of exercise were 162.1±1.2 mm Hg in GG homozygotes and 162.3± 1.4 mm Hg in T+ carriers (P=0.92). In subjects with a BMI ≥26 kg/m2, these mean levels were 163.8±1.4 and 172.9±1.7 mm Hg, respectively (P<0.0001).
Discussion
This study was conducted to investigate whether molecular variations at the ET-1 locus might be involved in the predisposition to MI and/or the determination of BP levels. The control samples of the ECTIM Study offered the opportunity of studying genetic determinants of BP in large MONICA population–based samples of middle-aged men, not selected in terms of hypertension. The entire coding sequence and part of the 5′ flanking region of the ET-1 gene were screened for molecular variation. Five polymorphisms were detected, none of which were in the sequence encoding the mature ET-1 peptide. The polymorphisms identified were not associated with MI, nor did they contribute to significant variations of BP levels in the population at large. As far as we know, only 2 studies have previously investigated a possible involvement of the ET-1 gene in hypertension. One small case-control study reported an association between the ET1/+138 polymorphism and hypertension,34 a finding that was not confirmed in our study. Another study found no effect for a Taq1 restriction fragment length polymorphism (whose position was not specified) on hypertension and BP levels.35
In the general population, the ET1/C198 polymorphism had no effect on BP levels, but this masked a strong interaction of genotype with BMI on BP. Actually, there was a steeper increase of BP levels with BMI in carriers of the T allele than in GG homozygotes. As a consequence of this interaction, the T allele was associated with a significant increase of SBP and DBP levels in overweight subjects (BMI ≥26 kg/m2), whereas no significant effect was observed in lean subjects (BMI <26 kg/m2). Given the strength of this interaction and its consistency across the 4 ECTIM populations, we determined whether it could be replicated in an independent MONICA population.30 In the Glasgow Heart Scan Study, subjects homozygous for the ET1/C198 T allele had significantly increased resting and exercise-induced BP levels, but unlike the ECTIM Study, the effect on resting BP was independent of BMI. However, when analyzing exercise-induced BP according to BMI, we again found a strong and similar interaction between the T allele and BMI.
Both studies suggest that obesity is a crucial factor influencing the association between the ET1/C198 polymorphism and BP. Two recent studies have shown that plasma ET-1 concentrations were raised in obesity-associated hypertension and that obesity was a stronger determinant of circulating ET-1 levels than hypertension.3637 In support of this, weight loss due to caloric restriction has been shown to be accompanied by a marked decrease in ET-1 levels, in both obese38 and nonobese subjects.36 These observations suggest that obesity might be a factor that enhances the expression of the ET-1 gene, possibly through an upregulation by insulin, which is known to stimulate ET-1 production.363839
The ET-1 gene may be involved in exercise-induced rise in BP. It has been demonstrated that plasma ET-1 concentrations were significantly increased after cycle exercise and that this alteration followed an increase in circulating norepinephrine levels, another substance known to stimulate ET-1 production.40 Obesity is characterized by an activation of the sympathetic nervous system414243 and therefore might increase norepinephrine-mediated ET-1 production due to exercise. Interestingly, it has been shown that after cycle exercise of 1 leg, an exercise-induced rise in ET-1 was observed in the nonworking leg but not in the working leg, suggesting a mechanism whereby the endothelin-induced vasoconstriction in nonworking muscles may contribute to the redistribution of blood flow to the working muscles.44
The ET1/C198 polymorphism is not located in regulatory regions of the ET-1 gene and therefore is unlikely to alter the gene expression in response to various stimulating factors. One possibility might be that although it is predictive of an amino acid change, this polymorphism has no functional role on its own but is a marker in linkage disequilibrium with an as yet unidentified functional mutation in the regulatory regions of the ET-1 gene. Another possibility might be that the ET1/C198 polymorphism affects the processing of the transcript of preproendothelin. Because this polymorphism has not been related to any intermediate biological phenotype, these interpretations remain speculative.
In conclusion, our results from 2 independent population-based studies suggest that the ET1/C198 polymorphism, or a polymorphism in linkage disequilibrium with it, is involved in the determination of BP levels in overweight people. However, this polymorphism was not associated with the risk of MI in the ECTIM Study.
Reprint requests to Laurence Tiret, INSERM U525, 17 rue du Fer à Moulin, 75005 Paris, France.
Figure 1. Genotype-specific regression slopes of SBP levels on BMI in control subjects of the ECTIM Study (slopes are adjusted for age and population). The symbol indicates the mean point in each genotype group
Figure 2. Genotype-specific regression slopes of maximum blood pressure (maxBP) levels achieved during treadmill exercise test on BMI in subjects of the Glasgow Heart Scan Study (slopes are adjusted for gender, age, and exercise time). The symbol indicates the mean point in each genotype group
| Characteristic | ET1/C198 Genotype | Test | ||||
|---|---|---|---|---|---|---|
| GG (n=454) | GT (n=265) | TT (n=41) | ||||
| Age, y | 53.2 (0.4) | 53.4 (0.5) | 54.8 (1.3) | P=0.52 | ||
| BMI, kg/m2 | 26.2 (0.2) | 26.8 (0.2) | 25.6 (0.6) | P=0.05 | ||
| SBP, mm Hg | 132.2 (0.9) | 134.0 (1.2) | 130.1 (3.0) | P=0.34 | ||
| DBP, mm Hg | 81.1 (0.6) | 82.9 (0.8) | 81.4 (2.0) | P=0.20 | ||
| Antihypertensive treatment, % | 18.7 | 20.8 | 17.1 | P=0.63 | ||
| Characteristic | Men | Women | Test1 | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| GG (n=360) | GT (n=225) | TT (n=34) | GG (n=376) | GT (n=250) | TT (n=37) | ||||||
| Age, y | 50.5 (0.7) | 52.1 (0.9) | 52.4 (2.4) | 50.5 (0.7) | 51.4 (0.9) | 52.0 (2.3) | P=0.27 | ||||
| BMI, kg/m2 | 26.2 (0.3) | 26.0 (0.3) | 27.4 (0.8) | 26.5 (0.2) | 26.3 (0.3) | 27.4 (0.8) | P=0.13 | ||||
| SBP, mm Hg | 134.6 (1.1) | 134.1 (1.3) | 143.3 (3.5) | 131.4 (1.0) | 132.0 (1.3) | 136.2 (3.3) | P=0.03 | ||||
| DBP, mm Hg | 79.7 (0.6) | 79.9 (0.8) | 85.8 (2.0) | 76.5 (0.6) | 77.2 (0.7) | 77.9 (1.9) | P=0.04 | ||||
| Antihypertensive treatment, % | 13.6 | 11.3 | 15.2 | 10.8 | 13.8 | 8.1 | P=0.95 | ||||
| Variable | Men | Women | Test1 | Test2 | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Genotype | N | Mean (SE) | N | Mean (SE) | ||||||
| Exercise duration, min3 | GG | 243 | 12.63 (0.13) | 258 | 11.13 (0.12) | |||||
| GT | 156 | 12.63 (0.16) | 172 | 11.11 (0.15) | ||||||
| TT | 19 | 13.25 (0.46) | 25 | 10.77 (0.40) | 0.97 | 0.30 | ||||
| Maximum heart rate, bpm4 | GG | 243 | 156.4 (1.0) | 258 | 156.5 (1.0) | |||||
| GT | 156 | 156.4 (1.3) | 172 | 159.4 (1.2) | ||||||
| TT | 19 | 155.8 (3.6) | 25 | 156.8 (3.1) | 0.36 | 0.40 | ||||
| Maximum BP, mm Hg4 | GG | 243 | 167.5 (1.4) | 258 | 158.1 (1.3) | |||||
| GT | 156 | 173.2 (1.8) | 172 | 159.6 (1.6) | ||||||
| TT | 19 | 175.9 (4.8) | 25 | 161.1 (4.2) | 0.03 | 0.31 | ||||
| Maximum BP adjusted for | GG | 243 | 165.4 (1.1) | 258 | 160.7 (1.1) | |||||
| baseline BP, mm Hg4 | GT | 156 | 170.8 (1.4) | 172 | 161.8 (1.3) | |||||
| TT | 19 | 169.6 (3.9) | 25 | 159.9 (3.4) | 0.03 | 0.17 | ||||
The recruitment in the ECTIM Study was supported by grants from the Squibb Laboratory, the British Heart Foundation, INSERM, and the “Institut Pasteur-Lille.” The Glasgow Heart Scan study was funded by the Chief Scientist Office of the Scottish Home and Health Department. The genetic program was supported by an agreement between INSERM and the Merck Sharpe and Dohme Chibret company.
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