Haplotypes of NOS3 Gene Polymorphisms in Dilated Cardiomyopathy
Haplotypes of NOS3 Gene Polymorphisms in Dilated Cardiomyopathy
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DOI：
10.1371/journal.pone.0070523
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发表时间：
2013-07-29
期刊：
影响因子：
3.7
通讯作者：
Nallari, Pratibha
中科院分区：
文献类型：
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作者：
Matsa, Lova Satyanarayana;Rangaraju, Advithi;Nallari, Pratibha
扩张型心肌病（DCM）的特征是收缩功能障碍，随后发生需要心脏移植的心力衰竭。通过鉴定肌节和细胞骨架基因的突变，很好地建立了遗传基础。修饰基因和环境因素也被认为在疾病的可变表达中起重要作用，因此涉及多种机制，其中一种机制是氧化应激。一氧化氮（NO）是内皮细胞的主要生理递质，作为血管扩张剂，具有多种抗动脉粥样硬化作用。内皮型一氧化氮合酶（NOS 3）基因的三种功能多态性，对59侧翼区的T-786 C、内含子4的27 bp VNTR和外显子7的G894 T进行基因分型，以确定它们在DCM中的作用。共纳入115份DCM样品和454份对照品。采用PCR-RFLP方法进行基因分型。等位基因和基因型频率在对照组和患者组中进行计算，并采用适当的统计检验。在DCM中观察到TC基因型（T-786 C）与比值比1.74（95%CI 1.14 - 2.67，p = 0.01）显著相关。同样，发现G894 T多态性的GT基因型频率具有统计学显著性（OR 2.10，95%CI 1.34-3.27，p = 0.0011），隐性等位基因T与DCM显著相关（OR 1.64，95%CI 1.18 - 2.30，p = 0.003）。携带隐性等位基因G894 T和T-786 C、C4 bT的单倍型与对照组相比，患DCM的风险增加7倍。因此，C4 bT单倍型可能是DCM的风险单倍型。我们的研究结果表明，NOS 3基因在疾病表型中的可能意义，其中NOS 3可能通过在心肌细胞中过量产生NO而在DCM相关的心力衰竭中协同发挥作用，导致心肌收缩力降低和收缩功能障碍，这是DCM表型的共同特征。
Dilated Cardiomyopathy (DCM) is characterized by systolic dysfunction, followed by heart failure necessitating cardiac transplantation. The genetic basis is well established by the identification of mutations in sarcomere and cytoskeleton gene/s. Modifier genes and environmental factors are also considered to play a significant role in the variable expression of the disease, hence various mechanisms are implicated and one such mechanism is oxidative stress. Nitric Oxide (NO), a primary physiological transmitter derived from endothelium seems to play a composite role with diverse anti-atherogenic effects as vasodilator. Three functional polymorphisms of endothelial nitric oxide synthase (NOS3) gene viz., T-786C of the 59 flanking region, 27bp VNTR in intron4 and G894T of exon 7 were genotyped to identify their role in DCM. A total of 115 DCM samples and 454 controls were included. Genotyping was carried out by PCR -RFLP method. Allelic and genotypic frequencies were computed in both control & patient groups and appropriate statistical tests were employed. A significant association of TC genotype (T-786C) with an odds ratio of 1.74, (95% CI 1.14 - 2.67, p = 0.01) was observed in DCM. Likewise the GT genotypic frequency of G894T polymorphism was found to be statistically significant (OR 2.10, 95% CI 1.34-3.27, p = 0.0011), with the recessive allele T being significantly associated with DCM (OR 1.64, 95% CI 1.18 - 2.30, p = 0.003). The haplotype carrying the recessive alleles of G894T and T-786C, C4bT was found to exhibit 7 folds increased risk for DCM compared to the controls. Hence C4bT haplotype could be the risk haplotype for DCM. Our findings suggest the possible implication of NOS3 gene in the disease phenotype, wherein NOS3 may be synergistically functioning in DCM associated heart failure via the excessive production of NO in cardiomyocytes resulting in decreased myocardial contractility and systolic dysfunction, a common feature of DCM phenotype.