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Interaction between PPARA genotype and beta-blocker treatment influences clinical outcomes following acute coronary syndromes.

ABSTRACT: beta-blockers (BB) are strongly recommended after an acute coronary syndrome (ACS), although all patients may not benefit. Causes for variable patient responses to BB are unknown. Given that myocardial ischemia and BB influence metabolic processes regulated by peroxisome proliferator-activated receptor alpha (PPARalpha), we hypothesized that interactions between polymorphisms of the PPARalpha gene (PPARA) and BB treatment would influence clinical outcome following ACS.Patients were prospectively enrolled into an ACS registry. A total of 735 ACS patients were genotyped. Mortality and cardiac rehospitalization through 1 year were analyzed in relation to PPARA genotype and BB prescription (597 BB; 138 no BB) at discharge.Significantly different outcomes associated with BB therapy were observed according to PPARA IVS7 2498 genotype (p = 0.002 for interaction). PPARA IVS7 2498 GG homozygous patients discharged on BB had decreased cardiac rehospitalization (hazard ratio [HR]: 0.52; 95% CI: 0.32-0.86; p = 0.011), while C allele carriers discharged on BB had nearly threefold increased cardiac rehospitalization (HR: 2.92; 95% CI: 1.32-6.92; p = 0.015; genotype interaction p = 0.0005) compared with patients not on BB. PPARA genotype was also associated with differences in PPARalpha expression, with significantly increased mRNA levels in myocardial samples from normal hearts among GC heterozygotes compared with GG homozygotes (p = 0.04). Transgenic mice with cardiac-specific overexpression of PPARalpha showed significantly reduced myocardial contractile and chronotropic responses to the beta-sympathomimetic dobutamine (p < 0.05) compared with wild-type littermates, supporting the hypothesis that increased PPARalpha levels result in a blunted beta-adrenergic response.PPARA IVS7 2498 genotype is associated with heterogeneity in 1-year outcome in response to BB among patients following ACS, and may predict which patients benefit from BB therapy, putatively related to the effect of myocardial PPARalpha expression on beta-adrenergic responsiveness.

SUBMITTER: Cresci S

PROVIDER: S-EPMC2586954 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Interaction between PPARA genotype and beta-blocker treatment influences clinical outcomes following acute coronary syndromes.

Cresci Sharon S Jones Philip G PG Sucharov Carmen C CC Marsh Sharon S Lanfear David E DE Garsa Adam A Courtois Michael M Weinheimer Carla J CJ Wu Jun J Province Michael A MA Kelly Daniel P DP McLeod Howard L HL Spertus John A JA

Pharmacogenomics 20081001 10

<h4>Aims</h4>beta-blockers (BB) are strongly recommended after an acute coronary syndrome (ACS), although all patients may not benefit. Causes for variable patient responses to BB are unknown. Given that myocardial ischemia and BB influence metabolic processes regulated by peroxisome proliferator-activated receptor alpha (PPARalpha), we hypothesized that interactions between polymorphisms of the PPARalpha gene (PPARA) and BB treatment would influence clinical outcome following ACS.<h4>Patients & ...[more]

PMID: 18855529

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Project description:UCP2 -866G>A (rs659366) has been implicated in cardiometabolic disease and represents a novel candidate gene for beta-blocker response, particularly among patients with diabetes. We assessed the function of -866G>A and its role as a modifier of beta-blocker treatment outcomes by diabetes status in an acute coronary syndrome (ACS) cohort.ACS patients with genetic samples and 12 months of follow-up for cardiac rehospitalizations or death (n=468) were assessed. The influence of -866G>A on beta-blocker treatment outcomes was evaluated in those with diabetes and without. To assess functional correlates of -866G>A, we compared uncoupling protein 2 (UCP2) expression in the skeletal muscle of obese participants by genotype and compared the activity of UCP2 luciferase promoters with -866G and -866A alleles.An interaction between -866G>A and beta-blocker treatment was found in individuals with diabetes (P=0.002) but not those without (P=0.79). Among G/G individuals with diabetes, discharge beta-blocker use was associated with an 80% reduction in cardiac rehospitalization (adjusted hazard ratio: 0.20; 95% confidence interval: 0.04-1.02). In contrast, among A-carrier patients with diabetes, there was an 11-fold increase in cardiac rehospitalizations with discharge beta-blocker therapy (adjusted hazard ratio: 11.75; 95% confidence interval: 1.28-108.2). Promoter activity assays showed that -866G had greater cyclic AMP response element binding protein-responsiveness compared with -866A, and compared with -866A carriers G/G individuals exhibited increased UCP2 expression in the skeletal muscle.We identified a significant interaction between -866G>A and beta-blocker response among ACS patients with diabetes. Furthermore, -866G conferred greater gene transcriptional activity than -866A in cell lines and in obese patients. These findings may help us gain insight into the mechanisms underlying the beneficial and detrimental effects of beta-blockers in those with diabetes.

Project description:ContextConflicting information exists about whether sex differences modulate short-term mortality following acute coronary syndromes (ACS).ObjectivesTo investigate the relationship between sex and 30-day mortality in ACS, and to determine whether this relationship was modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates.Design, setting, and participantsA convenience sample of patients pooled from 11 independent, international, randomized ACS clinical trials between 1993 and 2006 whose databases are maintained at the Duke Clinical Research Institute, Durham, North Carolina. Of 136 247 patients, 38 048 (28%) were women; 102 004 (26% women) with ST-segment elevation myocardial infarction (STEMI), 14 466 (29% women) with non-STEMI (NSTEMI), and 19 777 (40% women) with unstable angina.Main outcome measureThirty-day mortality following ACS.ResultsThirty-day mortality was 9.6% in women and 5.3% in men (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.83-2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR, 1.06; 95% CI, 0.99-1.15). A significant sex by type of ACS interaction was demonstrated (P < .001). In STEMI, 30-day mortality was higher among women (adjusted OR, 1.15; 95% CI, 1.06-1.24), whereas in NSTEMI (adjusted OR, 0.77; 95% CI, 0.63-0.95) and unstable angina, mortality was lower among women (adjusted OR, 0.55; 95% CI, 0.43-0.70). In a cohort of 35 128 patients with angiographic data, women more often had nonobstructive (15% vs 8%) and less often had 2-vessel (25% vs 28%) and 3-vessel (23% vs 26%) coronary disease, regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (P for interaction = .70).ConclusionsSex-based differences existed in 30-day mortality among patients with ACS and vary depending on clinical presentation. However, these differences appear to be largely explained by clinical differences at presentation and severity of angiographically documented disease.

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Interaction between PPARA genotype and beta-blocker treatment influences clinical outcomes following acute coronary syndromes.

Publications

Interaction between PPARA genotype and beta-blocker treatment influences clinical outcomes following acute coronary syndromes.

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