B-type natriuretic peptide (BNP) system is critical to cardiovascular physiological and pathological processes, especially in the development and progression of heart failure (HF) caused by dilated cardiomyopathy (DCM-HF).1,2 Single nucleotide polymorphism (SNP) in the non-coding region, especially the promoter region, might correlate well with plasma BNP levels, and potentially affect the susceptibility of DCM-HF, through interacting with transcription factor and regulating natriuretic peptide B (NPPB) gene transcription.3,4 Meanwhile, NPPB gene methylation might promote the process of DCM-HF development by dysregulating its gene transcription and affecting plasma BNP levels.5 This study demonstrated that: i) in all three SNP sites identified in the NPPB gene, mutational rs198389 in the promoter region promoted NPPB gene transcription through its combination with androgen receptor (AR); ii) as the critical transcription factor of NPPB gene, glucocorticoid receptor alpha (GR-ɑ) more obviously promoted NPPB gene transcription in combination with wild-type rs198389, and retinoid X receptor alpha (RXR-ɑ) more obviously inhibited NPPB gene transcription in combination with mutational rs198389; iii) NPPB gene methylation depressed NPPB gene transcription, and its demethylation accelerated NPPB gene unmethylation and transcription.