| Background and Object:Neuregulin-1/ErbB2/ErbB4 signaling pathway plays a critical role in the regulation of cardiac myocyte biology and normal heart function. It is not only crucial for the normal development of the embryonic heart, but also maintains the normal structure and function of the heart after birth and plays a role in mediating cellular adaptations to stress. Experimental rats in which the genes for NRG-1/ErbB2/ErbB4 had been inactivated presented with a series of dilated cardiomyopathy manifestations. Moreover, NRG-1/ErbB2/ErbB4 gene-defective myocardial cells were more susceptible to anthracycline’s toxicity, and myocardial fibers were abnormally arranged. Recombinant human NRG-1 was also found to be beneficial in heart failure treatment. Given the role of the NRG-1/ErbB2/ErbB4 signaling pathway in the pathogenesis of heart failure, our hypothesis was that different functional genotypes of the single nucleotide polymorphisms (SNP) in this signaling pathway might lead to different presentations of heart failure and might be associated with the susceptibility to heart failure. In this respect, we undertook this case-control study to examine whether polymorphisms in the NRG-1/ErbB2/ErbB4 genes were associated with the risk and prognosis of heart failure.Methods:Genotyping of thirteen single nucleotide polymorphisms (SNPs) in the NRG-1/ErbB2/ErbB4 genes was performed in 569 unrelated heart failure patients and 682 controls from the Northern Han Chinese population with the use of iPLEX SNP Genotyping analysis on a Sequenom MassARRAY(?) System. The SNPs were identified from the SNP database in the international HapMap project and National Center of Biotechnology Information with the minimum allele frequency greater than 0.05. The subjects’clinical data and follow-up outcomes were collected.Results:The A allele frequency of rs10932374 and the G allele frequency of rs1595064 in the ErbB4 gene were markedly lower in the HF-REF patients than in the control subjects (33.7% vs 37.7%, P=0.039; 44.5% vs 49.9%, P=0.007), while the T allele frequency of rs13003941 and the C allele frequency of rs1595065 were significantly higher in the HF-REF patients (33.4% vs 28.6%, P=0.014; 26.8% vs 22.1%, P=0.005).Logistic regression analysis indicated that the A allelic polymorphism of rs10932374 and the G allelic polymorphism of rs1595064 were significantly associated with reduced risk of heart failure (odds ratio,OR=0.84,95% CI:0.71-0.99, P=0.039; OR=0.80,95% CI:0.69-0.94, P=0.007, respectively); whereas the T allelic polymorphism of rs13003941 and the C allelic polymorphism of rs1595065 were significantly associated with increased risk of heart failure (OR=1.25,95% CI:1.05-1.50, P=0.014; OR=1.30,95% CI:1.08-1.56, P=0.005, respectively). After adjusting for the potential confounding effects of age, gender, BMI, smoking, drinking, hypertension history and uric acid, three allelic polymorphisms of rs10932374, rs1595064 and rs13003941 were still significantly associated with risk of heart failure. The C allelic polymorphism of rs1595065 was not associated with the risk of heart failure after adjusting the risk factors (OR=1.26,95% CI:0.98-1.62, P=0.069).Four polymorphisms in the ErbB4 gene were associated with risk of heart failure. Two polymorphisms, rs13003941 and rs1595065, were associated with increased risk of heart failure in both a dominant genetic model (OR=1.41,95% CI:1.11-1.78, P=0.004; OR=1.49,95% CI:1.19-1.87, P=0.000, respectively) and an additive genetic model (OR=1.25,95% CI: 1.05-1.50, P=0.013; OR=1.32,95% CI:1.09-1.60, P=0.004, respectively). The other two polymorphisms, rs10932374 and rsl595064, were associated with reduced risk of heart failure in both a recessive genetic model (OR=0.64,95% CI:0.46-0.90, P=0.009; OR=0.63,95% CI:0.48-0.83, P=0.001, respectively) and an additive genetic model (OR=0.85,95% CI:0.72-0.99, P=0.042; OR=0.81,95% CI:0.69-0.94, P=0.007, respectively).The A-G-G-T-T haplotype of rsl0932374-rs13003941-rs1595064-rs1595065-rs3748960 in the ErbB4 gene was the most prevalent. Its frequency was significantly lower in the patients than in the controls (case vs. control= 33% vs.37%, permutation P value = 0.045). Compared with the A-G-G-T-T haplotype, haplotype G-G-C-C-T increased the risk of heart failure (OR=1.35,95% CI:1.06-1.70, P=0.014). After adjusting for age and gender, this haplotype was still significantly associated with risk of heart failure (P=0.013). The T variant of rs13003941 was associated with larger left ventricle (dominant model, P=0.014; additive model, P=0.048), and increased risk of overall death (relative risk, RR=1.48,95%CI:1.01-2.18, P=0.045) and cardiovascular death (RR=1.56, 95% CI:1.04-2.33, P=0.03) after adjusting for age and gender. Mutant alleles of both rs1595065 and rs13003941 differed from their wild-type alleles in binding miRNA and might affect miRNA-binding site activity. NRG-1/ErbB2 gene polymorphisms were not associated with heart failure risk or prognosis.Conclusion:ErbB4 gene polymorphisms were associated with the risk, severity and prognosis of heart failure in the Northern Han Chinese population. |
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