ß-adrenergic receptor polymorphisms in susceptibility, response to treatment and prognosis in heart failure: implication of ethnicity.

Common functional polymorphisms in ß-adrenergic receptor (ßAR) genes have been associated with heart failure (HF) phenotypes and pharmacogenetic interactions with ßAR blockers. This study evaluated the association between ßAR polymorphisms and carvedilol drug response and prognosis in patients with HF. In this prospective cohort controlled study, 326 volunteers were enrolled [146 HF patients (ejection fraction (EF)<50% by Simpson) and 180 healthy controls]. Drug response was evaluated by echocardiography and outcomes were mortality and hospitalization. DNA was extracted from peripheral blood leukocytes, fragments were amplified by the polymerase reaction and genotyped by restriction fragment length polymorphism (RFLP) for Ser49Gly and Arg389Gly ßAR-1 polymorphisms and Gln27Glu and Arg16Gly ßAR-2 polymorphisms. The study population was in Hardy­Weinberg equilibrium. The survival rate was adjusted using the Kaplan-Meier method. HF patients showed the following characteristics: EF 35±9%, 69.9% male, age 59±13 years, 50.7% self-identified as black, 46% had ischemic etiology. The mean follow-up of 23 months showed 18 mortalities and 46 hospitalizations. The genotypes Glu27Glu (24.7 vs. 6.1%, p=0.0004) and Arg16Arg (72.6 vs. 22.8, p<0.0001) of ßAR2 polymorphisms and Gly49Gly (33.6 vs. 4.3%, p<0.0001) of the ßAR1 polymorphism were higher in HF patients compared with controls. Patients with hospital admission showed a significantly higher Gly389 allelic frequency (54.9 vs. 42.1%, p=0.039), and the trend prevailed among patients who succumbed to the disease (61.1%, p=0.047). Black patients with the Ser49Ser genotype showed a reduced survival compared with the Gly49Gly or Ser49Gly genotypes (p=0.028). There was no association between improved LVEF >20% and ßAR polymorphisms. HF patients with ß-blocker therapy and the Gly389 allele have reduced event-free survival compared to those carrying the Arg389 allele. Additionally, systolic HF outpatients undergoing ß-blocker therapy, self­identified as black and homozygous for Ser49Ser may have reduced event-free survival, while Glu27Glu, Arg16Arg and Gly49Gly genotypes may be associated with risk for HF.

Endothelial nitric oxide synthase Glu298Asp gene polymorphism in a multi-ethnical population with heart failure and controls.

Brazilian population has a multi-ethnical profile and the prevalence of endothelial nitric oxide synthase enzyme (eNOS) polymorphism in heart failure (HF) has not been previously studied. Therefore the present study assessed the association of eNOS Glu298Asp polymorphism in patients with HF and controls. In a crossover study, was analysed the distribution of the Glu298Asp in 100 outpatients with HF, and 103 healthy controls. Self-reported race were analyzed. Left atria and left ventricle diameters and ejection fraction were evaluated in patients group. Glu298Asp was analysed by polymerase chain reaction and restriction fragment length polymorphism. The patient's average age was 59 years, 66% males, 49% Afro-descendants. The allelic frequency in patient group was Glu298=72%/Asp298=28% and the genotype frequency (GF) was Glu298Glu:49%; Glu298Asp:47%; Asp298Asp:4%. In control group, 60% Glu298 and 40% Asp298; 35% Glu298Glu, 49.5% Glu298Asp and 15.5% Asp298Asp. The prevalence of allele Glu298 was significantly higher in patients (p=0.009) as genotype Glu298Glu (p=0.03). The Glu298 in Afro-Brazilians (79%) and white patients (67%) were similar, although there was significant difference (p=0.03) in GF Glu298Glu between Afro-Brazilians and whites. There was an increased prevalence of hypertension and increased atria in Glu298Glu patients comparing with combined genotype Glu298Asp and Asp298Asp. This study suggests a regional variation in the distribution of Glu298Asp. The comparison of this distribution in African-Brazilian suggests a synergistic effect of African-descendent, Glu298Glu genotype and HF. Also demonstrated an increased frequency of Glu298 and Glu298Glu, suggesting interaction of them with HF. In HF patients, the clinical, echocardiograph and genotype analysis suggests an association of Glu298 allele and hypertension.