Introduction The role of neuraminidases in cardiovascular disease has recently gained increasing attention. However, the association between neuraminidase gene polymorphisms and heart failure (HF) has not yet been investigated. Methods and Results Genotyping of nine single nucleotide polymorphisms (SNPs) in the NEU2/NEU3/NEU4 genes was performed in 610 HF patients and 600 healthy controls from the Southwest Han Chinese population using TaqMan SNP Genotyping Assay. Individuals carrying the A allele of rs11545301 had decreased risk of HF (additive model: OR=0.704, 95% CI=0.511–0.97; P = 0.032). While the C allele of rs2293763 increased the risk of HF in recessive model (OR=1.486, 95% CI=1.095–2.012; P = 0.011). Rs2233384, rs2233394 and rs2293763 were significantly associated with the mortality risk of HF in dominant model, both with and without adjustment for conventional risk factors (HR= 0.686, 95% CI= 0.52-0.906, P = 0.008 for rs2233384; HR= 1.357, 95% CI= 1.035-1.78, P = 0.027 for rs2233384 and HR= 0.76, 95% CI= 0.592-0.975; P = 0.031 for rs2293763). Conclusion Our findings demonstrated the association between a series of variants in NEU2/NEU4 genes and the risk or prognosis of HF in Han Chinese Population. These data suggested an important role of NEU2 and NEU4 in the pathogenesis of HF.

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