| 1. |
- Brändström, Helena, et al.
(författare)
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A single nucleotide polymorphism in the promoter region of the osteoprotegerin gene is related to intima-media thickness of the carotid artery in hypertensive patients : The Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA)
- 2004
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Ingår i: Blood Pressure. - : Informa UK Limited. - 0803-7051 .- 1651-1999. ; 13:3, s. 152-157
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Tidskriftsartikel (refereegranskat)abstract
- Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and in previous studies has been shown to regulate osteoclast activity and differentiation. Ablation of the OPG gene in mice results in calcification of the aorta and renal arteries. We have previously reported an association between a single nucleotide polymorphism in the promoter region of OPG and vascular morphology and function in healthy humans. The objective with this study was to confirm our previous results in a larger population, and in addition, to study subjects with hypertension. The OPG genotype was determined by restriction fragment length and the intima-media thickness (IMT) of the common carotid artery was measured by ultrasound in 100 patients with hypertension and left ventricular hypertrophy, and 75 healthy normotensive control subjects. In the hypertensive group subjects with the CC genotype (n=24) showed a significantly increased IMT compared to those with the TC (n=52, p=0.007) and TT (n=24, p=0.009) genotype, in the hypertensive group only (mean +/- SD for TT=0.88 +/- 0.21 mm, TC=0.90 +/- 0.16 mm, CC=1.05 +/- 0.31 mm). The allele distribution did not differ between hypertensive and control individuals. The present study confirms our previous finding and shows that polymorphism in the promoter region of OPG is associated with vascular morphology in hypertensive subjects.
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| 2. |
- Hallberg, Pär, et al.
(författare)
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Adipocyte-derived leucine aminopeptidase genotype and response to antihypertensive therapy
- 2003
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261 .- 1471-2261. ; 18:3, s. 11-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAdipocyte-derived leucine aminopeptidase (ALAP) is a recently identified member of the M1 family of zinc-metallopeptidases and is thought to play a role in blood pressure control through inactivation of angiotensin II and/or generation of bradykinin. The enzyme seems to be particularly abundant in the heart. Recently, the Arg528-encoding allele of the ALAP gene was shown to be associated with essential hypertension.MethodsWe evaluated the influence of this polymorphism on the change in left ventricular mass index in 90 patients with essential hypertension and echocardiographically diagnosed left ventricular hypertrophy, randomised in a double-blind study to receive treatment with either the angiotensin II type I receptor antagonist irbesartan or the beta1-adrenoceptor blocker atenolol for 48 weeks. Genyotyping was performed using minisequencing.ResultsAfter adjustment for potential covariates (blood pressure and left ventricular mass index at baseline, blood pressure change, age, sex, dose and added antihypertensive treatment), there was a marked difference between the Arg/Arg and Lys/Arg genotypes in patients treated with irbesartan; those with the Arg/Arg genotype responded on average with an almost two-fold greater regression of left ventricular mass index than patients with the Lys/Arg genotype (-30.1 g/m2 [3.6] vs -16.7 [4.5], p = 0.03).ConclusionsThe ALAP genotype seems to determine the degree of regression of left ventricular hypertrophy during antihypertensive treatment with the angiotensin II type I receptor antagonist irbesartan in patients with essential hypertension and left ventricular hypertrophy. This is the first report of a role for ALAP/aminopeptidases in left ventricular mass regulation, and suggests a new potential target for antihypertensive drugs.
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| 3. |
- Hallberg, Pär, et al.
(författare)
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B2 bradykinin receptor (B2BKR) polymorphism and change in left ventricular mass in response to antihypertensive treatment : results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial
- 2003
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Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 21:3, s. 621-4
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system, including left ventricular (LV) hypertrophy. Studies have demonstrated that bradykinin, through the B2 bradykinin receptor (B2BKR), mediates important cardiovascular effects that may protect against LV hypertrophy. Recently, a +9/-9 exon 1 polymorphism of the B2BKR was shown to be strongly associated with LV growth response among normotensive males undergoing physical training. We aimed to clarify whether the processes found in exercise-induced LV growth in normotensive people also occur in pathological LV hypertrophy. DESIGN AND METHODS: We determined the B2BKR genotype of 90 patients with essential hypertension and echocardiographically diagnosed LV hypertrophy, included in a double-blind study to receive treatment for 48 weeks with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol. RESULTS: B2BKR +9/+9 genotypes responded poorly in LV mass regression, independent of blood pressure reduction or treatment, as compared to the other genotypes (adjusted mean change in LV mass index = -10.0 +/- 4.6 versus -21.6 +/- 2.2 g/m2, P = 0.03). CONCLUSIONS: Our results suggest an impact of the B2BKR polymorphism on LV mass regression during antihypertensive treatment.
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| 4. |
- Hallberg, Pär, et al.
(författare)
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Gender-specific association between preproendothelin-1 genotype and reduction of systolic blood pressure during antihypertensive treatment : results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA)
- 2004
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Ingår i: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 27:5, s. 287-290
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Studies suggest that endothelin-1 contributes to the pathogenesis of hypertension. A G5665T gene polymorphism of preproendothelin-1 has been shown to be associated with higher blood pressure in overweight patients. No study has yet determined the effect of this polymorphism on the change in blood pressure during antihypertensive treatment.HYPOTHESIS:This study aimed to determine this effect in hypertensive patients with left ventricular (LV) hypertrophy during antihypertensive treatment with either irbesartan or atenolol.METHODS: We determined the preproendothelin-1 genotype using minisequencing in 102 patients with essential hypertension and LV hypertrophy verified by echocardiography, randomized in a double-blind fashion to treatment with either the AT1-receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol.RESULTS:The change in systolic blood pressure (SBP) after 12 weeks of treatment was related to the preproendothelin-1 genotype in men; after adjustment for potential covariates (age, blood pressure, and LV mass index at study entry, dose of irbesartan/atenolol, and type of treatment), those carrying the T-allele responded on average with a more than two-fold greater reduction than those with the G/G genotype (-21.9 mmHg [13.9] vs. -8.9 [2.3], p = 0.007). No significant differences in blood pressure change between G/G and carriers of the T-allele were seen among women.CONCLUSIONS:Our finding suggests a gender-specific relationship between the G5665T preproendothelin-1 polymorphism and change in SBP in response to antihypertensive treatment with irbesartan or atenolol, suggesting the endothelin pathway to be a common mechanism included in the hypertensive action of the drugs.
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| 5. |
- Hallberg, Pär, et al.
(författare)
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The CYP2C9 genotype predicts the blood pressure response to irbesartan : results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial
- 2002
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Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 20:10, s. 2089-2093
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The cytochrome P450 CYP2C9 enzyme (CYP2C9) metabolizes many clinically important drugs, for example, phenytoin, warfarin and the angiotensin II type 1 (AT(1)) receptor antagonists, losartan and irbesartan. Single nucleotide polymorphisms in the CYP2C9 gene result in the expression of three important variants, CYP2C9*1(wild-type), CYP2C9*2 and CYP2C9*3, the last two exhibiting reduced catalytic activity compared with the wild-type. The CYP2C9 genotype is known to determine sensitivity to and dose requirements for both warfarin and phenytoin, and also the rate of metabolism of losartan. However, its influence on clinical response to treatment with the AT(1) receptor antagonist, irbesartan, has not been investigated. OBJECTIVE: To determine whether the CYP2C9genotype influences the blood pressure-decreasing response to antihypertensive treatment with irbesartan. DESIGN AND METHODS: One hundred and two patients with essential hypertension and left ventricular hypertrophy were allocated randomly to groups to receive double-blind treatment with either irbesartan (n = 49) or the beta(1)-adrenergic receptor blocker, atenolol ( n= 53). Blood pressure was measured before and after 12 weeks of treatment. genotyping was performed using solid-phase minisequencing. RESULTS: The diastolic blood pressure (DBP) response differed in relation to the CYP2C9 genotype in patients given irbesartan: the reduction in patients with genotype CYP2C9*1/CYP2C9*1 (n = 33) was 7.5% and that with CYP2C9*1/CYP2C9*2 (n = 12) was 14.4% ( P= 0.036). A similar trend was seen for systolic blood pressure. In contrast, no relation was seen between the CYP2C9 genotype and blood pressure response to atenolol, a drug not metabolized via CYP2C9. CONCLUSIONS: The CYP2C9 genotype seems to predict the DBP response to irbesartan, but not to atenolol, in patients with essential hypertension.
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| 6. |
- Hallberg, Pär, et al.
(författare)
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Transforming growth factor beta1 genotype and change in left ventricular mass during antihypertensive treatment : results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA)
- 2004
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Ingår i: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 27:3, s. 169-73
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Angiotensin II, via the angiotensin II type 1 (AT1) receptor, may mediate myocardial fibrosis and myocyte hypertrophy seen in hypertensive left ventricular (LV) hypertrophy through production of transforming growth factor beta1 (TGF-beta1); AT1-receptor antagonists reverse these changes. The TGF-beta1 G + 915C polymorphism is associated with interindividual variation in TGF-beta1 production. No study has yet determined the impact of this polymorphism on the response to antihypertensive treatment. HYPOTHESIS: We aimed to determine whether the TGF-beta1 G + 915C polymorphism was related to change in LV mass during antihypertensive treatment with either an AT1-receptor antagonists or a beta1-adrenoceptor blocker. The polymorphism was hypothesized to have an impact mainly on the irbesartan group. METHODS: We determined the association between the TGF-beta1 genotype and regression of LV mass in 90 patients with essential hypertension and echocardiographically diagnosed LV hypertrophy, randomized in a double-blind study to receive treatment for 48 weeks with either the AT1-receptor antagonist irbesartan or the beta1-adrenoceptor blocker atenolol. RESULTS: Irbesartan-treated patients who were carriers of the C-allele, which is associated with low expression of TGF-beta1, responded with a markedly greater decrease in LV mass index (LVMI) than subjects with the G/G genotype (adjusted mean change in LVMI -44.7 g/m2 vs. -22.2 g/m2, p = 0.007), independent of blood pressure reduction. No association between genotype and change in LVMI was observed in the atenolol group. CONCLUSIONS: The TGF-beta1 G + 915C polymorphism is related to the change in LVMI in response to antihypertensive treatment with the AT1-receptor antagonist irbesartan.
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| 7. |
- Kurland, Lisa, et al.
(författare)
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Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response : result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial
- 2002
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Ingår i: American Journal of Hypertension. - : Elsevier. - 0895-7061 .- 1941-7225. ; 15:5, s. 389-93
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Our aim was to determine whether the aldosterone synthase (CYP11B2) -344 C/T polymorphism was associated with the blood pressure (BP)-lowering response to antihypertensive treatment. METHODS: Patients with mild-to-moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind study to receive treatment with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan (n = 43), or the beta1-adrenergic receptor blocker atenolol (n = 43). The aldosterone synthase (CYP11B2) -344 C/T polymorphism was analyzed using solid-phase minisequencing and related to BP reduction after 3 months treatment. Serum aldosterone levels were measured. RESULTS: After 3 months treatment the mean reductions in BP were similar for both treatment groups. When assessing the systolic BP reduction in the irbesartan group, patients with the TT variant had a more pronounced reduction (-21 +/- 19 SD mm Hg, n = 17) than both the TC (-14 +/- 18 mm Hg, n= 18) and CC (0 +/- 17 mm Hg, n = 8) genotypes (P = .04). There was no association between this polymorphism and the diastolic BP response. The -344 C/T polymorphism was not associated with the BP response to atenolol. Nor was it related to the baseline serum aldosterone level. CONCLUSIONS: The aldosterone synthase -344 C/T polymorphism was related to the BP-lowering response in hypertensive patients treated with the AT1-receptor antagonist irbesartan.
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| 8. |
- Kurland, Lisa, et al.
(författare)
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Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients
- 2001
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Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 19:10, s. 1783-1787
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To determine whether polymorphisms in the renin-angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol. DESIGN AND METHODS: Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the beta1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction. RESULTS: The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (-18 +/- 11 SD versus -7 +/- 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment. CONCLUSIONS: ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.
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| 9. |
- Kurland, Lisa, 1960-, et al.
(författare)
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Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment : results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial
- 2002
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Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 20:4, s. 657-663
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Our aim was to determine if gene polymorphisms in the renin-angiotensin-aldosterone system (RAAS) were related to the degree of change in left ventricular hypertrophy (LVH) during antihypertensive treatment. METHODS AND RESULTS: Patients with essential hypertension and echocardiographically diagnosed LVH were included in a double-blind study to receive treatment with either the angiotensin II type 1 receptor (AT1-receptor) antagonist irbesartan (n = 41), or the beta-1 adrenergic receptor blocker atenolol (n = 43) as monotherapy for 3 months. The angiotensinogen T174M and M235T, the angiotensin-converting enzyme I/D, the AT1-receptor A1166C and the aldosterone synthase (CYP11B2) -344 C/T polymorphisms were analysed and related to the change in left ventricular mass (LVM). Patients with the angiotensinogen 174 TM genotype treated with irbesartan responded with the greatest reduction in LVM (-23 +/- 31SD g/m2 for TM and +0.5 +/- 18 g/m2 for TT, P = 0.005), independent of blood pressure reduction. Both the angiotensinogen 235 T-allele (P = 0.02) and the AT1-receptor 1166 AC genotype responded with the greatest reduction in LVM when treated with irbesartan (-0.1 +/- 19 g/m2 for AA and -18 +/- 30 g/m2 for AC, P = 0.02), independent of blood pressure reduction. These polymorphisms were not associated with the change in LVM during treatment with atenolol. DISCUSSION: The angiotensinogen T174M and M235T and the AT1-receptor A1166C polymorphisms were related to the change in LVH during antihypertensive treatment with an AT1-receptor antagonist; of these angiotensinogen T174M was the most powerful. This highlights the role of the RAAS for left ventricular hypertrophy and the potential of pharmacogenetics as a tool for guidance of antihypertensive therapy.
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| 10. |
- Liljedahl, Ulrika, et al.
(författare)
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A microarray minisequencing system for pharmacogenetic profiling of antihypertensive drug response
- 2003
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Ingår i: Pharmacogenetics. - : Ovid Technologies (Wolters Kluwer Health). - 0960-314X .- 1473-561X. ; 13:1, s. 7-17
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to develop a microarray genotyping system for multiplex analysis of a panel of single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in blood pressure regulation, and to apply this system in a pilot study demonstrating its feasibility in the pharmacogenetics of hypertension. A panel of 74 SNPs in 25 genes involved in blood pressure regulation was selected from the SNP databases, and genotyped in DNA samples of 97 hypertensive patients. The patients had been randomized to double-blind treatment with either the angiotensin II type 1 receptor blocker irbesartan or the beta 1-adrenergic receptor blocker atenolol. Genotyping was performed using a microarray based DNA polymerase assisted 'minisequencing' single nucleotide primer extension assay with fluorescence detection. The observed genotypes were related to the blood pressure reduction using stepwise multiple regression analysis. The allele frequencies of the selected SNPs were determined in the Swedish population. The established microarray-based genotyping system was validated and allowed unequivocal multiplex genotyping of the panel of 74 SNPs in every patient. Almost 7200 SNP genotypes were generated in the study. Profiles of four or five SNP-genotypes that may be useful as predictors of blood pressure reduction after antihypertensive treatment were identified. Our results highlight the potential of microarray-based technology for SNP genotyping in pharmacogenetics.
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