Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) has crucial roles for myocardial development, cardiomyocyte energy metabolism and cell death/survival by regulating NAD+-dependent sirtuin-1 (SIRT1) deacetylase. This study aimed to determine if the single nucleotide polymorphisms (SNPs) of the NAMPT gene may affect the susceptibility and prognosis for patients with dilated cardiomyopathy (DCM) and to describe the association of serum NAMPT levels with clinical features of DCM. Three SNPs (rs61330082, rs2505568, and rs9034) were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method in a case-control study of 394 DCM patients and 395 controls from China. Serum NAMPT levels were measured by enzyme-linked immunosorbent assay kits. The homozygote for the minor allele at rs2505568 and rs9034 could not be detected in this study. Rs9034 T allele and CT genotype were associated with increased DCM risk (OR: 1.63, 95% CI = 1.16–2.27, p = 0.005 and OR: 1.72, 95% CI = 1.20–2.50, p = 0.0027, respectively). Nominally significant decreased DCM risk was found to be associated with the A allele and AT genotype of rs2505568 (OR: 0.48, 95% CI = 0.35–0.67, p < 0.0001 and OR: 0.44, 95% CI = 0.31–0.62, p < 0.0001, respectively), but it should be interpreted with caution because of Hardy-Weinberg disequilibrium in the control group. Of five haplotypes constructed, TAC (rs61330082-rs2505568-rs9034) was a protective haplotype to DCM (OR: 0.22, 95% CI = 0.13–0.39, p = 1.84 × 10−8). The Cox multivariate survival analysis indicated that the rs9034 CT genotype (hazard ratio (HR): 0.59, 95% CI = 0.37–0.96, p = 0.03) was an independently multivariate predictor for longer overall survival in DCM patients. Serum NAMPT levels were significantly higher in the DCM group than controls (p < 0.0001) and gradually increased with the increase of New York Heart Association grade in DCM patients. However, there was a lack of association of the three SNPs with serum NAMPT levels. Spearman correlation test revealed that the NAMPT level was positively associated with brain natriuretic peptide (r = 0.56, p = 0.001), left ventricular end-diastolic diameter (r = 0.293, p = 0.011) and left ventricular end-diastolic volume (r = 0.294, p = 0.011). Our study suggested that NAMPT may play an important role in the development of DCM.
Highlights
Dilated cardiomyopathy (DCM) is a heart muscle disorder characterized by dilatation and systolic impairment of the left or both ventricles in the absence of hypertension, coronary artery disease or valvular abnormalities [1]
SIRT1-deficient mice showed a progressive dilated cardiomyopathy strongly associated with mitochondrial dysfunction, and SIRT1 plays an essential role in the maintenance of mitochondrial integrity and modulates the Mef2 transcription factors in the heart [23]
Our study demonstrates for the first time that rs9034 of the Nicotinamide phosphoribosyltransferase (NAMPT) gene was associated with susceptibility to DCM, and TAC was a protective haplotype to DCM
Summary
Dilated cardiomyopathy (DCM) is a heart muscle disorder characterized by dilatation and systolic impairment of the left or both ventricles in the absence of hypertension, coronary artery disease or valvular abnormalities [1]. DCM is the most frequent cause of heart failure (HF) in the young [2] and the most common indication for cardiac transplantation [3]. Mutations in more than 50 genes have been implicated in the development of DCM. Genes encoding for sarcomeric, cytoskeletal, nuclear membrane, dystrophin-associated glycoprotein complex and desmosomal proteins are the principal genes involved [4]. These mutations explain only a minority of the etiology of DCM. Most DCMs are sporadic and nonfamilial with multifactorial causes linked to genetic susceptibility. Many genetic polymorphisms have been shown to be associated with an increased risk of developing DCM [5,6]. Genetic studies should not be restricted to familial DCM
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