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Matsa L.S.,Osmania University | Sagurthi S.R.,Osmania University | Ananthapur V.,Institute of Genetics and Hospital for Genetic Diseases | Nalla S.,CARE Hospitals | Nallari P.,Osmania University
Gene | Year: 2014

Dilated cardiomyopathy (DCM) is a myocardial disease of unknown etiology with left ventricular dilatation and impaired myocardial contractility leading to heart failure. It is considered to be a multifactorial disorder with the interplay of both genetic and environmental factors. One of the possible genes implicated in DCM is endothelin 1 (EDN1). The genetic variants of EDN1 may be involved in the pathophysiology of DCM hence the entire EDN1 gene was screened to examine for the possible genotypic associations with DCM. A total of 115 DCM patients and 250 control subjects were included in the present study. PCR based SSCP analysis was carried out followed by commercial sequencing. Screening of EDN1 revealed two common and two rare polymorphisms. Allelic and genotypic frequencies were estimated in patient and control groups by appropriate statistical tests. The heterozygotes of insertion variation (+. 138A) were found to exhibit four-fold increase risk to DCM (OR=4.12, 95% CI 2.10-8.08; p=0.0001). The two rare variants (G>A transition (rs150035515) at c.90 and C>T transition (rs149399492) at c.119) observed in the present study were found to be unique in DCM. The secondary mRNA structures of these variations were found to have less free energy than wild type. The haplotype analysis revealed 4A-T to be risk haplotype for DCM (OR 5.90, 95% CI 2.29-15.25, p=0.0001). In conclusion, EDN1 polymorphisms (+. 138A, A30A, T40I) appear to play a significant role in the pathogenesis of DCM, as they influence the stability of protein. The increased EDN1 production may lead to constriction of coronary arteries, reducing coronary blood flow which may in turn increase the load on left ventricle, impairing contractility of the heart resulting in a DCM phenotype, an end stage of heart failure. © 2014 Elsevier B.V.


Munshi A.,Institute of Genetics and Hospital for Genetic Diseases | Kaul S.,Nizam's Institute of Medical Sciences
Neurology India | Year: 2010

Stroke or "brain attack" is a complex disease caused by a combination of multiple risk factors. It has major social and economic consequences. Various epidemiological studies in families and twins have revealed that there is a genetic component to stroke risk. Stroke may be the outcome of single gene disorders or more commonly, a polygenic multifactorial disease. Mutations in several candidate genes have been found to be associated with stroke. However, association studies in population-based samples have failed to identify reliable disease markers. The publication of the "Human Genome Project" has indeed improved our knowledge about the potential role of genetics in complex disorders including stroke. Rapidly expanding field of genetics is in a state of transforming medicine into a new kind in future, the individualized medicine, using tailor made drugs according to the genetic makeup of the individuals. However, this involves integrating genome wide genetic information with medical information. The first genome wide association study on ischemic stroke has been published recently. Further studies will hopefully tell us how far the genetic information will assist us to tailor clinical and therapeutic decisions to an individual's genotype.


Matsa L.S.,Osmania University | Rangaraju A.,Osmania University | Vengaldas V.,Osmania University | Latifi M.,Osmania University | And 3 more authors.
PLoS ONE | Year: 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. © 2013 Matsa et al.


Masoodi T.A.,King Saud University | Shaik N.A.,King Abdulaziz University | Shafi G.,King Saud University | Shafi G.,Institute of Genetics and Hospital for Genetic Diseases | And 4 more authors.
Gene | Year: 2012

To gain insight into the possible origin of the hemagglutinin of 2009 outbreak, we performed its comparative analysis with hemagglutinin of influenza viral strains from 2005 to 2008 and the past pandemics of 1977, 1968, 1957 and 1918. This insilico analysis showed a maximum sequence similarity between 2009 and 1918 pandemics. Primary structure analysis, antigenic and glycosylation site analyses revealed that this protein has evolved from 1918 pandemic. Phylogenetic analysis of HA amino acid sequence of 2009 influenza A(H1N1) viruses indicated that this virus possesses a distinctive evolutionary trait with 1918 influenza A virus. Although the disordered sequences are different among all the isolates, the disordered positions and sequences between 2009 and 1918 isolates show a greater similarity. Thus these analyses contribute to the evidence of the evolution of 2009 pandemic from 1918 influenza pandemic. This is the first computational evolutionary analysis of HA protein of 2009 H1N1 pandemic. © 2011 Elsevier B.V.


Ramachandran G.,Osmania University | Kumar M.,All India Institute of Medical Sciences | Selvi Rani D.,Center for Cellular and Molecular Biology | Annanthapur V.,Institute of Genetics and Hospital for Genetic Diseases | And 3 more authors.
PLoS ONE | Year: 2013

Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disorder of the myocardium which is hypertrophied resulting in arrhythmias and heart failure leading to sudden cardiac death (SCD). Several sarcomeric proteins and modifier genes have been implicated in this disease. Troponin I, being a part of the Troponin complex (troponin I, troponin C, troponin T), is an important gene for sarcomeric function. Four mutations (1 novel) were identified in Indian HCM cases, namely, Pro82Ser, Arg98Gln, Arg141Gln and Arg162Gln in Troponin I protein, which are in functionally significant domains. In order to analyse the effect of the mutations on protein stability and protein-protein interactions within the Troponin complex, an in silico study was carried out. The freely available X-ray crystal structure (PDB ID: 1JIE) was used as the template to model the protein followed by loop generation and development of troponin complex for both the troponin I wild type and four mutants (NCBI ID: PRJNA194382). The structural study was carried out to determine the effect of mutation on the structural stability and protein-protein interactions between three subunits in the complex. These mutations, especially the arginine to glutamine substitutions were found to result in local perturbations within the troponin complex by creating/removing inter/intra molecular hydrogen bonds with troponin T and troponin C. This has led to a decrease in the protein stability and loss of important interactions between the three subunits. It could have a significant impact on the disease progression when coupled with allelic heterogeneity which was observed in the cases carrying these mutations. However, this can be further confirmed by functional studies on protein levels in the identified cases. © 2013 Ramachandran et al.


Sharma V.,Institute of Genetics and Hospital for Genetic Diseases | Nehru B.,Panjab University | Munshi A.,Institute of Genetics and Hospital for Genetic Diseases | Jyothy A.,Institute of Genetics and Hospital for Genetic Diseases
Methods and Findings in Experimental and Clinical Pharmacology | Year: 2010

Pentylenetetrazol (PTZ)-induced oxidative stress results in disturbance of the antioxidant enzyme status accompanied by neuronal injury and the development of epilepsy in rats. The present study evaluated the antioxidant effects of curcumin against PTZ-induced convulsions. Over a period of 30 days, i.p. injections of subconvulsive doses of PTZ on alternate days resulted in the development of a well-known kindling model of epilepsy. Spectrophotometric analysis revealed a markedly elevated activity of the antioxidant enzymes malondialdehyde (MDA), catalase and glutathione S-transferase (GST) in the cerebrum and cerebellum of epileptic rats due to PTZ-induced oxidative stress. Oral supplementation of curcumin at a dose of 2 g/kg for 30 days resulted in a transient decrease in MDA, catalase and GST levels in the rat cerebrum and cerebellum. Piperine (20 mg/kg orally) was administered along with curcumin to enhance the bioavailability of the latter up to 20-fold more. Combined treatment with curcumin and carbamazepine (3.6 mg/kg orally) also gave similar results, indicating that the potent antioxidant curcumin can be used as an adjuvant in antiepileptic therapy. © 2010 Prous Science, S.A.U. or its licensors.


Medikare V.,Osmania University | Kandukuri L.R.,Center for Cellular and Molecular Biology | Ananthapur V.,Institute of Genetics and Hospital for Genetic Diseases | Deenadayal M.,Infertility Institute and Research Center | Nallari P.,Osmania University
Journal of Reproduction and Infertility | Year: 2011

Uterine leiomyomas/fibroids are the most common pelvic tumors of the female genital tract. The initiators remaining unknown, estrogens and progesterone are considered as promoters of fibroid growth. Fibroids are monoclonal tumors showing 40-50% karyotypically detectable chromosomal abnormalities. Cytogenetic aberrations involving chromosomes 6, 7, 12 and 14 constitute the major chromosome abnormalities seen in leiomyomata. This has led to the discovery that disruptions or dysregulations of HMGIC and HMGIY genes contribute to the development of these tumors. Genes such as RAD51L1 act as translocation partners to HMGIC and lead to disruption of gene structure leading to the pathogenesis of uterine fibroids. The mechanism underlying this disease is yet to be identified. The occurrence of PCOLCE amid a cluster of at least eight Alu sequences is potentially relevant to the possible involvement of PCOLCE in the 7q22 rearrangements that occur in many leiomyomata. PCOLCE is implicated in cell growth processes. Involvement of Alu sequences in rearrangements can lead to the disruption of this gene and, hence, loss of control for gene expression leading to uncontrolled cell growth. This can also lead to the formation of fibroids. Though, cytogenetics provides a broad perspective on uterine fibroid formation, further molecular analysis is required to understand the etiopathogenesis of uterine fibroids.


PubMed | Institute of Genetics and Hospital for Genetic Diseases
Type: Journal Article | Journal: Indian journal of cancer | Year: 2016

Gastric cancer (GC) is the third most common cancer in India and is mediated by multiple genetic, epigenetic and environmental risk factors. A single nucleotide polymorphism rs3025058 at -1171 of the stromelysin-1 (matrix metalloproteinase [MMP]-3) promoter is resulting due to insertion/deletion of adenine thought to have an impact on increasing the risk for tumor formation.This study is aimed to understand the role of stromelysin-1 rs3025058 (-1171, 5A/6A) promoter polymorphism in the etiology of GC in Indian population.Genomic DNA was isolated from blood samples of the GC patients and controls. The genotyping of stromelysin-1 rs3025058 (-1171, 5A/6A) promoter polymorphism was carried out by amplification refractory mutation system-polymerase chain reaction method followed by agarose gel electrophoresis.The frequency of 5A/5A, 5A/6A, and 6A/6A genotypes in GC patients were 7.69%, 76.92%, and 15.38%, while in controls were 5.31%, 86.73%, and 7.96%, respectively. There was a significant difference in the distribution of 5A/6A genotype in patients compared to the controls (P < 0.05).This study showed an increased frequency of heterozygotes for stromelysin-1 rs3025058 and thought to be involved in the etiology of GC.


PubMed | Institute of Genetics and Hospital for Genetic Diseases and Osmania University
Type: | Journal: EXCLI journal | Year: 2016

miRNAs have been found to play a major role in cardiomyopathy, a heart muscle disorder characterized by cardiac dysfunction. Several miRNAs including those involved in heart development are found to be dysregulated in cardiomyopathy. These miRNAs act either directly or indirectly by controlling the genes involved in normal development and functioning of the heart. Indirectly it also targets modifier genes and genes involved in signaling pathways. In this review, miRNAs involved in heart development, including dysregulation of miRNA which regulate various genes, modifiers and notch signaling pathway genes leading to cardiomyopathy are discussed. A study of these miRNAs would give an insight into the mechanisms involved in the processes of heart development and disease. Apart from this, information gathered from these studies would also generate suitable therapeutic targets in the form of antagomirs which are chemically engineered oligonucleotides used for silencing miRNAs.


PubMed | Sir Ronald Ross Institute of Tropical and Communicable Diseases, Institute of Genetics and Hospital for Genetic Diseases, Merck And Co., Institute of Oncology & Regional Cancer Center and Mediciti Institute of Medical science MIMS Campus
Type: | Journal: Nitric oxide : biology and chemistry | Year: 2016

Cervical cancer is caused by infection with high risk human papillomavirus (HR-HPV). Inducible nitric oxide synthase (iNOS), a soluble factor involved in chronic inflammation, may modulate cervical cancer risk among HPV infected women. The aim of the study was to measure and correlate plasma nitrite/nitrate levels with tissue specific expression of iNOS mRNA among women with different grades of cervical lesions and cervical cancer. Tissue biopsy and plasma specimens were collected from 120 women with cervical neoplasia or cancer (ASCUS, LSIL, HSIL and invasive cancer) and 35 women without cervical abnormalities. Inducible nitric oxide synthase (iNOS) mRNA from biopsy and plasma nitrite/nitrate levels of the same study subjects were measured. Single nucleotide polymorphism (SNP) analysis was performed on the promoter region and Ser608Leu (rs2297518) in exon 16 of the iNOS gene. Differences in iNOS gene expression and plasma nitrite/nitrate levels were compared across disease stage using linear and logistic regression analysis. Compared to normal controls, women diagnosed with HSIL or invasive cancer had a significantly higher concentration of plasma nitrite/nitrate and a higher median fold-change in iNOS mRNA gene expression. Genotyping of the promoter region showed three different variations: A pentanucleotide repeat (CCTTT) n, -1026T>G (rs2779249) and a novel variant -1153T>A. These variants were associated with increased levels of plasma nitrite/nitrate across all disease stages. The higher expression of iNOS mRNA and plasma nitrite/nitrate among women with pre-cancerous lesions suggests a role for nitric oxide in the natural history of cervical cancer.

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