Polymorphisms of norepinephrine transporter and adrenergic receptor α1D are associated with the response to β-blockers in dilated cardiomyopathy

Abstract

Recent clinical trials have clearly demonstrated that the administration with b-blockers decreases the mortality in the patients with chronic heart failure (CHF). However, significant heterogeneity exists in the effectiveness of b-blockers among individual cases. We focused on 39 polymorphisms in 16 genes related to adrenergic system and investigated their association with the response to b-blockers among 80 patients with CHF owing to idiopathic dilated cardiomyopathy. The polymorphisms of NET T-182C (P ¼ 0.019), ADRA1D T1848A (P ¼ 0.023) and ADRA1D A1905G (P ¼ 0.029) were associated with the improvement of left ventricular fractional shortening (LVFS) by b-blockers. Furthermore, combined genotype analysis of NET T-182C and ADRA1D T1848A revealed a significant difference in LVFS improvement among genotype groups (P ¼ 0.011). These results suggest that NET (T-182C) and ADRA1D (T1848A and A1905G) polymorphisms are predictive markers of the response to b-blockers. Genotyping of these polymorphisms may provide clinical insights into an individual difference in the response to the b-blocker therapy in CHF.

Pharmacogenomics of Adrenergic Receptors; from Hypertension to Heart Failure

“…For example, the concentrations of NE in synaptic cleft are likely to be altered by its reuptake through NE transporter (NET). Indeed, we have reported the association between the NET gene polymorphism and β-blocker response [57]. Moreover, the involvement of the genes responsible for post-synaptic signaling pathway, such as G protein-coupled receptor kinase 5 [58], remains to be fully addressed.…”

Impact of Synergistic Polymorphisms in Adrenergic Receptor-Related Genes and Cardiovascular Events in Patients With Dilated Cardiomyopathy

“…17 The Figure 1. The ADRB1 Ser49 carrier, 8 ADRB1 Arg389 carrier, 14 and NET-182CC genotype 16 were defined as the predicted risk genotypes. (A) No cardiovascular events occurred in patients with fewer than 2 predicted risk genotypes.…”

“…BNP plasma level was also a significant predictor (adjusted RR, 1.001; 95% CI, 1.000-1.002; P=0.008). 16 were defined as the predicted risk genotypes. Analyses were conducted on the basis of the number of predicted risk genotypes a patient carried.…”

“…15 In addition, the NET T-182C polymorphism has been associated with response to β-blockers; patients with the NET−182CC genotype are resistant to β-blocker therapy. 16 An allele frequency analysis demonstrated that the frequency of the ADRB1 Gly49 allele was 0.17, and was lower in Asians (0.14) than in Caucasians (0.12-0.16) and African Americans (0.23-0.28); the frequency of the ADRB1 Gly389 allele was 0.20, and was lower in Asians (0.20-0.30) than in Caucasians (0.24-0.34) and African Americans (0.39-0.46), and the frequency of the NET-182C allele was 0.41, and was higher in Asians (0.37-0.44) than in Caucasians (0.27) and African Americans (0.15). 11 The frequencies of these adrenergic-related polymorphisms were not significantly different from those previously reported in Japanese individuals.…”

“…15 The NET-182CC genotype has been reported to be resistant to β-blocker therapy. 16 We hypothesized that a combination of polymorphisms that result in increased synaptic norepinephrine release and enhanced receptor function would predispose patients with DCM to cardiovascular events. Therefore, we evaluated the effect of polymorphisms in the adrenergic receptor-related genes ADRB1 and NET on cardiovascular event-free survival in patients with DCM.…”