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Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.
Van Driest, SL, Sleeper, LA, Gelb, BD, Morris, SA, Dietz, HC, Forbus, GA, Goldmuntz, E, Hoskoppal, A, James, J, Lee, TM, et al
The Journal of pediatrics. 2020;:213-220.e5
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Abstract
OBJECTIVE To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
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Anti-hypertensive strategies in patients with MEtabolic parameters, DIabetes mellitus and/or NephropAthy (the M E D I N A study).
Spinar, J, Vitovec, J, Soucek, M
Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2014;(3):412-21
Abstract
AIMS: The primary questions asked by the MEDINA (MEtabolic parameters, DIabetes mellitus and NephropAthy) study are: 1) Do angiotensin converting enzyme inhibitors (ACE-I) have any advantages over angiotensin receptor blockers (ARB)? 2) Should the other drug for combination be a diuretic or a calcium-channel blocker (CCB)? 3) How are the risks reduced by the co administration of a statin? METHODS A total of 439 hypertensive patients with metabolic syndrome and/or diabetes mellitus were randomized to 2 groups: group 1--ramipril (ACE-I) or perindopril and group 2--losartan (ARB). Hydrochlorothiazide (diuretic) or amlodipine (CCB) were added to both groups. As a third step, a statin was added. RESULTS Blood pressure decreased 24.1/13.3 mmHg in the ACE inhibitor group and 25.9/13.5 in the losartan group. The difference was insignificant. Adding either hydrochlorothiazide or amlodipin was equally effective. There were no significant differences on metabolic parameters in the trial arms. Cholesterol level decreased by 0.95 mmol/L in the ACE-I group and 1.02 mmol/L in the ARB group (ns). CONCLUSION MEDINA has so far confirmed the equivalence of ACE-I and ARB in hypertension treatment. Adding either diuretic or CCB was equally effective. Our data support the current recommendations on adding a statin to reduce cardiovascular risk.
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11beta-hydroxysteroid dehydrogenase activity in proteinuric patients and the effect of angiotensin-II receptor blockade.
Kerstens, MN, Buter, H, Navis, GJ, Dullaart, RP
European journal of clinical investigation. 2002;(7):513-8
Abstract
BACKGROUND It has been suggested that an altered setpoint of the 11betaHSD-mediated cortisol to cortisone interconversion towards cortisol contributes to sodium retention in nephrotic syndrome patients. We studied the parameters of 11betaHSD activity in proteinuric patients, in particular its activity at the kidney level. We also studied the effect of angiotensin-II receptor blockade on the parameters of 11betaHSD activity. MATERIALS AND METHODS Serum cortisol/cortisone ratio and the urinary ratios of (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone [(THF + allo-THF)/THE] and of urinary free cortisol/free cortisone (UFF/UFE) were measured in eight proteinuric patients and compared with eight matched, healthy subjects. Patients were subsequently studied after 4 weeks' treatment with losartan 50 mg day-1 and placebo, respectively. RESULTS No significant differences between the proteinuric patients and the healthy subjects were observed in the serum cortisol, serum cortisone, serum cortisol to cortisone ratio, or in the urinary excretions of THF, allo-THF, THE, sum of cortisol metabolites, or the (THF + allo-THF)/THE ratio. Urinary free cortisol excretion and the UFF/UFE ratio were lower in the proteinuric patients than in the healthy subjects (56 +/- 21 vs. 85 +/- 24 pmol min-1, P < 0.05, and 0.39 +/- 0.07 vs. 0.63 +/- 0.28, P < 0.05, respectively). Mean arterial pressure and proteinuria were reduced significantly during losartan treatment, but without concomitant changes in peripheral cortisol metabolism. CONCLUSIONS Increased renal inactivation of cortisol in proteinuric patients does not support the contention that altered 11betaHSD activity contributes to sodium retention in patients with nephrotic syndrome. Losartan 50 mg d.d. reduces mean arterial pressure and proteinuria, but does not exert a significant effect on the cortisol to cortisone interconversion.