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