β-adrenergic receptor polymorphisms in susceptibility, response to treatment and prognosis in heart failure: Implication of ethnicity

Abstract

Common functional polymorphisms in β-adrenergic receptor (βAR) genes have been associated with heart failure (HF) phenotypes and pharmacogenetic interactions with βAR blockers. This study evaluated the association between βAR 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 βAR-1 polymorphisms and Gln27Glu and Arg16Gly βAR-2 polymorphisms. The study population was in Hardy‑Weinberg 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 βAR2 polymorphisms and Gly49Gly (33.6 vs. 4.3%, p<0.0001) of the βAR1 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 βAR polymorphisms. HF patients with β-blocker therapy and the Gly389 allele have reduced event-free survival compared to those carrying the Arg389 allele. Additionally, systolic HF outpatients undergoing β-blocker therapy, self‑identified 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.

Race, Common Genetic Variation, and Therapeutic Response Disparities in Heart Failure

“…In BEST, there was no effect of the ADRB1 Ser49Gly polymorphism on bucindolol vs. placebo treatment effects in either AA or EA patients, with respective interaction p-values of 0.23 and 0.74 for ACM/HFH events. In AA patients, the hazard ratio was numerically higher in 49Gly carriers (1.26 [95% confidence interval 0.60–2.63]) compared with 49Ser homozygotes (0.72 [0.42–1.26]), indicating a trend for AA ADRB1 49Gly carriers to do worse on bucindolol, the opposite of the result with carvedilol in the Brazilian study (75). A Swedish study that did not report racial demographics but was presumably conducted in predominately EA patients found a therapeutic advantage to the the 49Gly genotype in patients treated with low doses of open-label metoprolol, which disappeared on higher doses (76).…”

“…There are conflicting reports of effects of the ADRB1 Ser49Gly polymorphism on β-blocker effect. A recent report found that open-label carvedilol-treated, Brazilian, AA patients who were 49Gly carriers had improved hospitalization-free survival compared with 49Ser homozygotes, while non-black patients treated with the same 25 mg bi-daily target dose showed no difference between genotypes (75). However, in a large, 75%-EA HF patient population studied prospectively and treated with carvedilol or metoprolol, no effect of ADRB1 Ser49Gly was found, including no racial interaction (73).…”

Genetic parallels of heart failure and chronic obstructive pulmonary disease

“…Обследование 56 пациен-тов европейского происхождения позволило установить, что высвобождение сердечного норадреналина и ЧСС были значительно выше у лиц с генотипом Arg16Arg гена ADRB2 в сравнении с Arg16Gly и Gln27Gln [8]. Представлены данные о бóльшей встречаемости геноти-пов Glu27Glu и Arg16Arg гена ADRB2 у пациентов с ХСН по сравнению со здоровыми лицами [9]. В исследова-нии, проведенном Г. П. Арутюновым Л. Н. Гончаровой, А. Ю. Постновым (2012), выявлено, что изменение пара-метров гемодинамики у пациентов мордовской наци-ональности (повышение САД и ДАД) при сочетании неблагоприятных генотипов DD гена ACE и Glu27Glu гена ADRB2 могут быть расценены как предикторы развития СН у пациентов с АГ [10].…”

Association between β1 adrenergic receptor gene Arg389Gly polymorphism and risk of heart failure: a meta-analysis

“…Based on the inclusion criteria, only six case-control studies (Small et al, 2002;Covolo et al, 2004;Nonen et al, 2005;Yu et al, 2006;Biolo et al, 2008;Pereira et al, 2013) with full text were included in this meta-analysis and 68 studies were excluded. The flow chart of study selection is summarized in Figure 1.…”