Norepinephrine and epinephrine induced distinct 2 adrenoceptor ...
OIII-B-2A haplotype of β2-adrenoceptor is associated with the increased risk for transplant or...
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OIII-B-1 BETA ADRENERGIC RECEPTORS POLYMORPHISMS ARE ASSOCIATED WITH RESPONSE TO BETA-BLOCKER THERAPY IN THE INTERNATIONAL VERAPAMIL SR-TRANDOLAPRIL STUDY (INVEST). Y. Gong, PhD, A. L. Beitelshees, PharmD, MPH, L. A. Stauffer, T. Y. Langaee, PhD, R. M. Cooper-DeHoff, PharmD, C. J. Pepine, MD, J. A. Johnson, PharmD, University of Florida, Washington University, Gainesville, FL. PURPOSE: To test the hypothesis that polymorphisms (SNPs) of 1 and 2 adrenergic receptors (ADRB1 & 2) are associated with the number of drugs needed to reach BP control in the -blocker arm of INVEST, which enrolled patients with hypertension and coronary artery disease (CAD). METHODS: DNA samples were obtained from 3012 patients who received atenolol, with addition of diuretic then ACE inhibitor if needed for BP control or per treatment guideline. Five SNPs were genotyped by Pyrosequencing: ADRB1 S49G, R389G; ADBR2 G16R, Q27E, C523A. Logistic regression was performed to model the number of drugs taken at the time of BP control with genotypes/ haplotypes adjusting for age, gender, BMI and other common con- founding factors of CAD. RESULTS: G389 and the ADRB2 haplotype G16-E27-C523 were associated with the need for more drugs to control BP. G389 homozygotes were more likely to require more drugs to control BP than R389 homozygotes (odds ratio 1.31 [1.04-1.66]) and heterozy- gotes (1.35 [1.07, 1.70]), as were patients with 2 (vs. 0) copies of ADRB2 haplotype GEC (1.43 [1.11-1.85]). Patients with higher baseline systolic BP, BMI 30, diabetes, history of heart failure were also more likely to need more drugs to control BP than those without these risk factors. CONCLUSIONS: These data suggest that ADRB1 G389 and ADRB2 haplotype GEC may affect variable BP response to atenolol therapy in older hypertensives with CAD, thus influencing the num- ber of drugs needed to control BP in a -blocker-based drug regimen. OIII-B-2 A HAPLOTYPE OF 2 -ADRENOCEPTOR IS ASSOCIATED WITH THE INCREASED RISK FOR TRANSPLANT OR DEATH IN HEART FAILURE PATIENTS. J. Shin, PharmD, M. T. Lob- meyer, BSPharm, Y. Gong, PhD, I. Zineh, PharmD, T. Y. Langaee, PhD, H. N. Yarandi, PhD, D. F. Pauly, MD, PhD, J. M. Aranda, MD, R. S. Schofield, MD, J. A. Hill, MD, MS, J. A. Johnson, PharmD, University of Florida, Gainesville, FL. BACKGROUND: Heart failure (HF) is characterized by neuro- hormonal activation of sympathetic nervous and renin-angiotensin systems. We tested whether genetic polymorphisms in these systems are associated with death or heart transplantation in patients with HF. METHODS: 227 HF patients were enrolled from a tertiary care HF clinic and followed for outcomes every 6 months for up to 4 years. We genotyped 8 polymorphisms in 6 genes including: 1 adrenergic receptor (ADRB1, S49G and R389G), 2 adrenergic re- ceptor (ADRB2, G16R and Q27E), 2c adrenergic receptor (ADRA2C, Insertion/Deletion (I/D) 322-325), angiotensinogen (AGT, M235T), angiotensin receptor type 1 (AGTR1, A1166C), and angio- tensin converting enzyme (ACE, I/D in intron 16). HAP software was used for haplotype assignment for ADRB1 and ADRB2. Cox propor- tional hazard regression was performed to model the outcomes with genotypes/haplotypes, adjusting for non-genetic predictors of HF. RESULTS: During a median 2.5 year follow-up period, 78 pa- tients had an adverse outcome. Ninety five percent and 81% of the patients received an ACE inhibitor/angiotensin receptor blocker and a -blocker at baseline, respectively. Significant predictors are shown in the Table. The ADRB2 RQ haplotype was the only genotype/ haplotype associated with adverse outcomes. Variable Hazard ratio 95% confidence interval P-value NYHA class 2.56 1.84-3.56 0.0001 Creatinine clearance 0.99 0.98-0.99 0.0016 Sodium 0.91 0.86-0.97 0.0019 Male gender 2.33 1.33-4.10 0.0032 ADRB2 RQ haplotype 1.40 1.01-1.93 0.047 CONCLUSIONS: In addition to other traditional predictors, ADRB2 haplotype may have a significant effect on risk for heart transplant/death in HF patients who receive contemporary HF phar- macotherapy. CLINICAL PHARMACOLOGY & THERAPEUTICS P30 American Society for Clinical Pharmacology and Therapeutics FEBRUARY 2006
Transcript of OIII-B-2A haplotype of β2-adrenoceptor is associated with the increased risk for transplant or...
OIII-B-1BETA ADRENERGIC RECEPTORS POLYMORPHISMS ARE
ASSOCIATED WITH RESPONSE TO BETA-BLOCKER THERAPYIN THE INTERNATIONAL VERAPAMIL SR-TRANDOLAPRILSTUDY (INVEST). Y. Gong, PhD, A. L. Beitelshees, PharmD,MPH, L. A. Stauffer, T. Y. Langaee, PhD, R. M. Cooper-DeHoff,PharmD, C. J. Pepine, MD, J. A. Johnson, PharmD, University ofFlorida, Washington University, Gainesville, FL.
PURPOSE: To test the hypothesis that polymorphisms (SNPs) of�1 and �2 adrenergic receptors (ADRB1 & 2) are associated with thenumber of drugs needed to reach BP control in the �-blocker arm ofINVEST, which enrolled patients with hypertension and coronaryartery disease (CAD).
METHODS: DNA samples were obtained from 3012 patientswho received atenolol, with addition of diuretic then ACE inhibitor ifneeded for BP control or per treatment guideline. Five SNPs weregenotyped by Pyrosequencing: ADRB1 S49G, R389G; ADBR2G16R, Q27E, C523A. Logistic regression was performed to modelthe number of drugs taken at the time of BP control with genotypes/haplotypes adjusting for age, gender, BMI and other common con-founding factors of CAD.
RESULTS: G389 and the ADRB2 haplotype G16-E27-C523were associated with the need for more drugs to control BP. G389homozygotes were more likely to require more drugs to control BPthan R389 homozygotes (odds ratio 1.31 [1.04-1.66]) and heterozy-gotes (1.35 [1.07, 1.70]), as were patients with 2 (vs. 0) copies ofADRB2 haplotype GEC (1.43 [1.11-1.85]). Patients with higherbaseline systolic BP, BMI 30, diabetes, history of heart failurewere also more likely to need more drugs to control BP than thosewithout these risk factors.
CONCLUSIONS: These data suggest that ADRB1 G389 andADRB2 haplotype GEC may affect variable BP response to atenololtherapy in older hypertensives with CAD, thus influencing the num-ber of drugs needed to control BP in a �-blocker-based drug regimen.
OIII-B-2A HAPLOTYPE OF �2-ADRENOCEPTOR IS ASSOCIATED
WITH THE INCREASED RISK FOR TRANSPLANT OR DEATHIN HEART FAILURE PATIENTS. J. Shin, PharmD, M. T. Lob-meyer, BSPharm, Y. Gong, PhD, I. Zineh, PharmD, T. Y. Langaee,PhD, H. N. Yarandi, PhD, D. F. Pauly, MD, PhD, J. M. Aranda, MD,R. S. Schofield, MD, J. A. Hill, MD, MS, J. A. Johnson, PharmD,University of Florida, Gainesville, FL.
BACKGROUND: Heart failure (HF) is characterized by neuro-hormonal activation of sympathetic nervous and renin-angiotensinsystems. We tested whether genetic polymorphisms in these systemsare associated with death or heart transplantation in patients with HF.
METHODS: 227 HF patients were enrolled from a tertiary careHF clinic and followed for outcomes every 6 months for up to 4years. We genotyped 8 polymorphisms in 6 genes including: �1
adrenergic receptor (ADRB1, S49G and R389G), �2 adrenergic re-ceptor (ADRB2, G16R and Q27E), �2c adrenergic receptor(ADRA2C, Insertion/Deletion (I/D) 322-325), angiotensinogen (AGT,M235T), angiotensin receptor type 1 (AGTR1, A1166C), and angio-tensin converting enzyme (ACE, I/D in intron 16). HAP software wasused for haplotype assignment for ADRB1 and ADRB2. Cox propor-tional hazard regression was performed to model the outcomes withgenotypes/haplotypes, adjusting for non-genetic predictors of HF.
RESULTS: During a median 2.5 year follow-up period, 78 pa-tients had an adverse outcome. Ninety five percent and 81% of thepatients received an ACE inhibitor/angiotensin receptor blocker anda �-blocker at baseline, respectively. Significant predictors are shownin the Table. The ADRB2 RQ haplotype was the only genotype/haplotype associated with adverse outcomes.
VariableHazard
ratio95% confidence
interval P-value
NYHA class 2.56 1.84-3.56 �0.0001Creatinine clearance 0.99 0.98-0.99 0.0016Sodium 0.91 0.86-0.97 0.0019Male gender 2.33 1.33-4.10 0.0032ADRB2 RQ haplotype 1.40 1.01-1.93 0.047
CONCLUSIONS: In addition to other traditional predictors,ADRB2 haplotype may have a significant effect on risk for hearttransplant/death in HF patients who receive contemporary HF phar-macotherapy.
CLINICAL PHARMACOLOGY & THERAPEUTICSP30 American Society for Clinical Pharmacology and Therapeutics FEBRUARY 2006
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