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Haplotypes of NOS3 gene polymorphisms in dilated cardiomyopathy.

ABSTRACT: 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.

SUBMITTER: Matsa LS

PROVIDER: S-EPMC3726655 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Haplotypes of NOS3 gene polymorphisms in dilated cardiomyopathy.

Matsa Lova Satyanarayana LS Rangaraju Advithi A Vengaldas Viswamitra V Latifi Mona M Jahromi Hossein Mehraban HM Ananthapur Venkateshwari V Nallari Pratibha P

PloS one 20130729 7

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 physiolog ...[more]

PMID: 23923002

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Project description:Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University Aim To evaluate the Association of rs1042713 polymorphism of the ADRB2 gene with dilated idiopathic cardiomyopathy (DCMP) and myocardial dilation of ischemic origin (DMI). Subjects and methods The study included patients with ICMP and DMI in the number of 221 people. The average age of the subjects was in the range of 55.30 ± 9.69 years. We divided the patients into 2 groups: the first – patients diagnosed with idiopathic dilatation cardiomyopathy and the second-patients with myocardial dilatation of ichemic origin. The number of patients in the first group was 111, including 99 men (89.2%) and 12 women (10.8%). The average age of patients in this group is 51.73 ± 9.74 years, in men 51.00 ± 8.96 years, in women 57.75 ± 3.71 years. The second group included patients with myocardial dilatation of ischemic origin. Their number is 110 people, including 100 men (91.5%) and 10 women (8.5%). The average age of respondents is 58.68 ± 8.38 years, for men 58.29 ± 8.46 years, for women 62.90 ± 6.29 years. The control group included patients who had no manifestations of cardiovascular diseases. Their number is 121 people (average age 53.6 ± 4.8 years). The patients underwent laboratory and instrumental studies, as well as molecular and genetic studies of the 16 AG polymorphism of the ADRB2 gene (rs1042713). All patients underwent coronary angiography. Based on the anamnesis data and instrumental studies, those patients who could be said to have no risk factors for the development of dilatation of the heart cavities were identified in the first group. And those patients who were reliably diagnosed with CHD were in the second group, that is, dilatation of the heart cavities is due to a previous myocardial infarction, existing angina pectoris. Results In the group with DCMP 10.8% of patients were carriers of the common homozygous 16AA genotype, the heterozygous 16AG genotype-48.6%, and the rare homozygous 16GG genotype-40.5%. In the control group 11.8% of patients were identified as carriers of a homozygous genotype by a common allele, and 47.5% were carriers heterozygous genotype, and homozygous genotype for a rare allele – 40.7%. The analysis non revealed a statistically significant decrease in the frequency of carrying the homozygous 16GG genotype in patients with DCMP compared to the control group of the rs1042713 polymorphism of the ADRB2 gene. In the group with DM IG, there was no association with the rs1042713 polymorphism of the ADRB2 gene. Conclusion A statistically significant association of rs1042713 of the ADRB2 gene with DCMP was not found. The association of DMI c rs1042713 could not be confirmed.

Project description:Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed familial DCM (FDC). FDC may account for 20-48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise) and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant.

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Haplotypes of NOS3 gene polymorphisms in dilated cardiomyopathy.

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Haplotypes of NOS3 gene polymorphisms in dilated cardiomyopathy.

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