Department of Genetics, Osmania University, Hyderabad, Andhra Pradesh, India.
PLoS One. 2013 Jul 29;8(7):e70523. doi: 10.1371/journal.pone.0070523. Print 2013.
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 5' 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.
扩张型心肌病（DCM）的特征是收缩功能障碍，随后心力衰竭需要心脏移植。通过鉴定肌节和细胞骨架基因/的突变，已经很好地确定了遗传基础。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，因此涉及各种机制，其中一种机制是氧化应激。一氧化氮（NO），一种源自内皮的主要生理递质，似乎具有多种抗动脉粥样硬化作用，作为血管扩张剂。内皮型一氧化氮合酶（NOS3）基因的三个功能多态性，即 5'侧翼区的 T-786C、内含子 4 中的 27bpVNTR 和外显子 7 中的 G894T，被基因分型以确定它们在 DCM 中的作用。共纳入 115 例 DCM 样本和 454 例对照。通过 PCR-RFLP 法进行基因分型。在对照组和患者组中计算了等位基因和基因型频率，并进行了适当的统计检验。在 DCM 中观察到 TC 基因型（T-786C）与 1.74 的优势比相关（95%CI 1.14-2.67，p=0.01）。同样，G894T 多态性的 GT 基因型频率也具有统计学意义（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）。与对照组相比，携带 G894T 和 T-786C 隐性等位基因的单体型 C4bT 显示出 7 倍的 DCM 风险。因此，C4bT 单体型可能是 DCM 的风险单体型。我们的发现表明 NOS3 基因可能参与疾病表型，其中 NOS3 可能通过在心肌细胞中过度产生 NO 导致心肌收缩力和收缩功能下降，从而协同作用于 DCM 相关心力衰竭，这是 DCM 表型的共同特征。
