Pratibha Nallari - Academia.edu (original) (raw)

Papers by Pratibha Nallari

Research paper thumbnail of © Kamla-Raj 2009 Int J Hum Genet, 9(3-4): 263-267 (2009) Pro and Anti-Oxidants in Cardiomyopathy

Free radicals play an essential role in maintaining the physiological condition of the body and o... more Free radicals play an essential role in maintaining the physiological condition of the body and oxidative stress is a result of an imbalance between free radicals and protective endogenous antioxidants, mostly associated with inflammatory disorders. Since cardiomyopathy is also an inflammatory disorder, the role of pro and anti oxidants is executed. Overall 180 cases (83 HCM and 97 DCM cases) and 100 healthy volunteers were included in the study. 5ml of venous blood samples were collected for the analysis of Malondialdehyde, Nitric oxide and Ceruloplasmin levels. MDA was found to be high in HCM whereas NO and Cp levels were high in DCM. Based on the findings it can be concluded that, Hypertrophic cardiomyopathy can results due to an imbalance in pro-oxidants while Dilated cardiomyopathy is an end result of oxidative stress. Hence the pro-oxidants MDA and NO, and antioxidant ceruloplasmin levels, may serve as prognostic indicators in hypertrophic and dilated cardiomyopathy, with fail...

Research paper thumbnail of miRNA regulation during cardiac development and remodeling in cardiomyopathy

miRNAs have been found to play a major role in cardiomyopathy, a heart muscle disorder characteri... more 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.

Research paper thumbnail of 5HTT Promoter Polymorphism in Idiopathic Pulmonary Arterial Hypertension

INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2011

Corneal dystrophies are defined as a group of inherited corneal disorders characterized by opacif... more Corneal dystrophies are defined as a group of inherited corneal disorders characterized by opacification of the cornea. Initial classification of corneal dystrophies was based on the layer of cornea involved but with the advent of better technology, a larger picture has evolved that includes both phenotypic and genotypic variants. With the evolving knowledge, a revised classification has been proposed by the International Committee for Classification of Corneal Dystrophies (IC3D). This classification has taken into account the clinical, histologic and genetic basis of the disease, integrating them into one. Our understanding of corneal dystrophies has reached new heights with mutations identified in at least 14 genes. Even though there has been a vast addition of information to the database, we still come across new variants which may seem enigmatic phenotypically. With the additional new information refining the molecular basis, there is a need to explore further the underlying molecular pathology so as to enable the possibility of better treatment modalities to the affected patients and their families. In view of the recent advances, we hereby review the dystrophies with an aim to provide updated information on the clinical and molecular aspects of corneal dystrophies which will aid in their differential diagnosis and management.

Research paper thumbnail of Superoxide Dismutase–A Genetic Marker in Cardiomyopathies

INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2003

Cardiomyopathies are a heterogeneous group of heart muscle disorders responsible for a great deal... more Cardiomyopathies are a heterogeneous group of heart muscle disorders responsible for a great deal of morbidity and mortality. Dilated, hypertrophic and restrictive are the three major categories of cardiomyopathies. Since reactive oxygen species has been implicated in wide range of genetic disorders and the role of antioxidant like superoxide dismutase as a scavenger has been highlighted, the present study envisages on identifying the specific electromorphic association of superoxide dismutase with cardiomyopathies and to delineate the genetic heterogeneity based on specific alleles at risk. Phenotyping was carried out on 8% PAGE of the red cell membrane samples following Davies (1964) and Beauchamp's (1975) protocols. Blood samples from 62 dilated cardiomyopathy, 80 hypertrophic cardiomyopathy and 86 healthy individuals were collected from CARE Hospitals and voluntary blood donor camps, Hyderabad. Significant association of homozygous SOD A*1 (χ 2 = 7.58) alleles with dilated cardiomyopathy and heterozygous SOD A*2-1 (χ 2 = 5.89) alleles with hypertrophic cardiomyopathy was observed, resulting in significant deviation of allelic frequency in cardiomyopathy group compared to the control group highlighting that individuals carrying SOD A*1 (χ 2 = 7.588) and SOD A*2-1 (χ 2 = 5.89) alleles may be at a greater risk for dilated and hypertrophic cardiomyopathy respectively. Thus SOD as a genetic marker may help in risk prediction and in delineating genetic heterogeneity of the condition and the role of superoxide dismutase with specific electromorphic association in influencing endogenous nitric oxide production and energy pathways by altering the structure and function of the cell membranes is discussed.

Research paper thumbnail of Pro and Anti-Oxidants in Cardiomyopathy

INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2009

Research paper thumbnail of Genetic Markers in Idiopathic Pulmonary Arterial Hypertension (IPAH)

INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2009

Idiopathic pulmonary arterial hypertension (IPAH) is a rare disorder with abnormally raised pulmo... more Idiopathic pulmonary arterial hypertension (IPAH) is a rare disorder with abnormally raised pulmonary arterial pressure. In IPAH, the trigger of the endothelial injury may result from oxidative stress, hypoxia, shear stress, inflammation in conjunction with genetic susceptibility. These epigenetic factors may have an influence on cell growth, differentiation and normal homeostatic functions of the endothelium, by altering endothelial permeability, production of growth factors and coagulation factors. Lung inflammation can lead to increased levels of oxidants that may also contribute to the development of IPAH. When the production of ROS exceeds, the capacity of the cell to detoxify them decreases and the resulting oxidative stress may be harmful to the integrity of biological tissue. Since in IPAH there is disruption of pulmonary artery vasculature, the generation of free radicals may further aggravate tissue injury and in view of its role in defensive mechanism, qualitative variation of SOD, CAT, AAT in IPAH is investigated in the present study to correlate specific electromorphic associations in its etiopathogenesis. In conclusion the present study revealed that Oxidative stress pathway (ROS/RNS) and inflammatory components may act as modifiers in pathogenicity of IPAH.

Research paper thumbnail of Association of Polymorphic Antioxidant Enzymes with Dilated Cardiomyopathy

INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2009

Despite considerable public awareness and technological advances that foster early diagnosis and ... more Despite considerable public awareness and technological advances that foster early diagnosis and aggressive therapeutic interventions, heart failure, which results as a final outcome from an underlying cardiovascular disorder remains a critical and an unsolved problem. Among the various cardiomyopathies, Dilated cardiomyopathy with an obscure etiology is known to be the leading cause of heart failure and sudden cardiac death among young adults and children. Studies related to the molecular basis of the condition have implicated oxidative stress pathways, apart from primary disease causing sarcomeric, cytoskeletal and mitochondrial gene mutations in the disease onset. The present study aims to evaluate the role of oxidative stress markers in 97 DCM patients and 105 control individuals to identify specific electromorphic association of superoxide dismutase, catalase and alpha-1-antitrypsin with the disease. Our study has revealed an association of SODA2, catalase HPII and AAT 'M' and 'Z' alleles with DCM, thereby resulting in inefficient scavenging of the free radicals, which may confer decreased protection against oxidative stress induced tissue injury in the disease pathogenesis. The involvement of SOD and AAT in apoptotic pathway and as immunomodulators is also emphasized.

Research paper thumbnail of Variants of PGIS and PPARγ in Idiopathic Pulmonary Arterial Hypertension

International Journal of Genomic Medicine, 2015

J o u rn al of C li n ic al & M e d ic a l G enom ic s

Research paper thumbnail of Implication of hsp70 gene polymorphisms in Arrhythmogenic right ventricular cardiomyopathy/dysplasia

JOURNAL OF HEART AND CARDIOLOGY, 2015

Introduction: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized... more Introduction: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by initial fibrofatty replacement of the right ventricle. Mutations in the Desmosomal and non desmosomal apart from modifier genes are known to be involved in the pathogenesis of the ARVC/D. One such modifier gene identified is HSP70 which plays an important role in cardio-protection. The present study investigates the role of Hsp70 polymorphisms in ARVC/D disease severity. Methods: Analysis of 100 control samples and 33 ARVC/D patients for 3 polymorphic loci was carried out by PCR-RFLP. Statistical analysis was carried out by SNPSTAT and haploview to analyze the genotypic data generated. Results: Our study revealed a statistically significant association of GC genotype (HSP70-1 +190G/C) [OR 2.93,95%CI 1.08-8.00, p=0.035] and TC genotype (HSP70-hom +2437T/C) [OR 2.04, 95% CI 1.01-4.55, p=0.045] with risk to develop ARVC/D. The haplotype frequency of CGT was also found to be higher in patients compared to controls, strengthening the synergistic effect of HSP70 family in ARVC/D. Conclusions: The present investigation revealed the importance of HSP70 polymorphisms in the pathogenesis of the ARVC/D. The results highlight a modifier role of HSP70 polymorphisms in ARVC/D etiopathogenesis, as the synergistic action of these polymorphisms may inhibit the HSP70 protein to perform its regular role, which in turn may trigger inflammation and apoptosis, hence the muscle tissue may be replaced by fibrofatty tissue.

Research paper thumbnail of Endothelin-1 and endothelial nitric oxide polymorphisms in idiopathic pulmonary arterial hypertension

International journal of molecular epidemiology and genetics, Jan 15, 2010

Idiopathic Pulmonary arterial hypertension (IPAH) is a debilitating disease associated with very ... more Idiopathic Pulmonary arterial hypertension (IPAH) is a debilitating disease associated with very poor prognosis. The disease is characterised by endothelial dysfunction, smooth muscle proliferation and insitu thrombosis in the pulmonary artery, eventually leading to right ventricular failure. Two of the key endothelial mediators implicated in the pathogenesis of IPAH are endothelin-1 (EDN1) and nitric oxide (NO). EDN1 is a potent endogenous vasoconstrictor whereas NO is a vasodilator. In the present study screening of the EDN1 gene (EDN1) and NOS3 polymorphisms was taken up, to evaluate their association with IPAH. A significant association of EDN1 3A/4A polymorphism (+138 A; rs10478694) (OR-3.485; CI-1.254, 9.999; p=0.013) and EDN1 Lys198Asn polymorphism (G/T, rs5370) (OR-3.378, CI-1.104, 10.582; p=0.03) with IPAH was observed. Our results indicate that EDN1 polymorphisms in interaction with other genetic markers may play a significant role in individual's susceptibility to the...

Research paper thumbnail of The genetic bases of uterine fibroids; a review

Journal of reproduction & infertility, 2011

Uterine leiomyomas/fibroids are the most common pelvic tumors of the female genital tract. The in... more 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% karyo-typically 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 c...

Research paper thumbnail of Genetic variations of α-cardiac actin and cardiac muscle LIM protein in hypertrophic cardiomyopathy in South India

Experimental and clinical cardiology, 2012

Hypertrophic cardiomyopathy (HCM) is a disease of the heart muscle, with an autosomal dominant mo... more Hypertrophic cardiomyopathy (HCM) is a disease of the heart muscle, with an autosomal dominant mode of inheritance. It is also known as the 'disease of the sarcomere', and is a major cause of morbidity and mortality worldwide. Mutations in the sarcomeric genes have been largely implicated in the manifestation of HCM. Modifier genes and environmental factors, along with causative mutation, add to the cumulative effect of the disease. In the present study, the role of the cardiac actin gene and the cardiac muscle LIM protein as contributors to HCM - through genetic variation - has been elucidated by screening the entire coding region in 100 control and 100 HCM subjects through polymerase chain reaction-based single-strand conformation polymorphism analysis and direct sequencing. The authors could not find any novel or reported exonic variations in any of the genes in the studied population; however, intronic variations were revealed in the cardiac actin gene through direct seq...

Research paper thumbnail of Modifier Genes in Hypertrophic Cardiomyopathy Patients of South Indian Cohort

International Journal of Genetics and Genomics, 2014

Hypertrophic cardiomyopathy is an autosomal dominant disorder, characterized by thickening of the... more Hypertrophic cardiomyopathy is an autosomal dominant disorder, characterized by thickening of the myocardium with a variable clinical course. Mutations in 14 sarcomeric genes have been implicated resulting in phenotypic and genotypic heterogeneity. The phenotypic expression of HCM is not only determined by the sarcomeric gene mutations but the genetic predilection of an individual also account for the inter-individual variability and genes with such functional variants that affect phenotypic expression are referred to as Modifier genes. Hence genetic variants of Angiotensin converting enzyme (ACE-2), Tumor necrosis factor-alpha (TNF-α) and Heat shock protein-70 (HSP70) genes have been considered in the present study to understand their role as modifiers of HCM. The study was carried out by Genotyping of 100 HCM and 100 controls by Polymerase chain reaction based restriction fragment length polymorphism analysis. The present study revealed a significant association of the HSP70-1 and HSP70-2 polymorphisms while ACE-2 and TNF-α genes were found to be statistically insignificant. However patients with the rare/variant genotypes were observed to have stronger clinical manifestations and echocardiographic parameters. This was further confirmed by Linkage disquillibrium analysis wherein individuals with the haplotypes GCGC and GCGT seemed to have increased susceptibility to HCM. The MDR analysis revealed a synergistic interaction of TNF-α with ACE-2 and HSP70 polymorphisms indicating their modifying effect in the presence of other environmental factors. Hence the present study emphasized the role of ACE-2, TNF-α and HSP70 polymorphisms as modifiers of the phenotypic expression in conjunction with other sarcoemric mutations and single nucleotide variations.

Research paper thumbnail of A Novel Arginine to Tryptophan (R144W) Mutation in Troponin T (cTnT) Gene in an Indian Multigenerational Family with Dilated Cardiomyopathy (FDCM)

PLoS ONE, 2014

Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in s... more Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in sarcomeric protein genes have been associated with this disease. Our aim in the present study is to investigate the genetic variations in Troponin T (cTnT) gene and its association with dilated cardiomyopathy (DCM) in south-Indian patients. Analyses of all the exons and exon-intron boundaries of cTnT in 147 DCM and in 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL; of which, polymorphic SNPs were compared with the HapMap population data. Interestingly, a novel R144W mutation, that substitutes polar-neutral tryptophan for a highly conserved basic arginine in cTnT, altering the charge drastically, was identified in a DCM, with a family history of sudden-cardiac death (SCD). This mutation was found within the tropomyosin (TPM1) binding domain, and was evolutionarily conserved across species, therefore it is expected to have a significant impact on the structure and function of the protein. Family studies had revealed that the R144W is co-segregating with disease in the family as an autosomal dominant trait, but it was completely absent in 207 healthy controls and in 162 previously studied HCM patients. Further screening of the proband and three of his family members (positive for R144W mutant) with eight other genes b-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3, did not reveal any disease causing mutation, proposing the absence of compound heterozygosity. Therefore, we strongly suggest that the novel R144W unique/private mutant identified in this study is associated with FDCM. This is furthermore signifying the unique genetic architecture of Indian population.

Research paper thumbnail of Haplotypes of NOS3 Gene Polymorphisms in Dilated Cardiomyopathy

PLoS ONE, 2013

Dilated Cardiomyopathy (DCM) is characterized by systolic dysfunction, followed by heart failure ... more 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.

Research paper thumbnail of A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia

Research paper thumbnail of Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

Journal of Human Genetics, 2003

The disease is characterized by extreme clinical and morphological heterogeneity, ranging from be... more The disease is characterized by extreme clinical and morphological heterogeneity, ranging from benign to severe, and is further complicated by a variable age of presentation.

Research paper thumbnail of Etiopathogenesis of arrhythmogenic right ventricular cardiomyopathy

Journal of Human Genetics, 2005

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterised by progressive fibrofatty... more Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterised by progressive fibrofatty replacement of right ventricular myocardium. Earlier studies described ARVC as non-inflammatory, non-coronary disorder associated with arrhythmias, heart failure and sudden death due to functional exclusion of the right ventricle. Molecular genetic studies have identified nine different loci associated with ARVC; accordingly each locus is implicated for each type of ARVC (ARVC1-ARVC9). So far five genes have been identified as containing pathogenic mutations for ARVC. Though mutations in each of the gene/s indicate disruption of different pathways leading to the condition, the exact pathogenesis of the condition is still obscure. This review tries to understand the pathogenesis of the condition by examining the individual proteins implicated and relate them to the pathways that could play a role in the aetiology of the condition. Cardiac ryanodine receptor (RYR-2), which regulates intra-cellular Ca 2+ concentration by releasing Ca 2+ reserves from the sarcoplasmic reticulum (SR), was the first gene for ARVC. The mutation in this gene is believed to disrupt coupled gating of RYR-2, causing after-depolarisation, leading to arrhythmias followed by structural changes due to altered intra-cellular Ca 2+ levels. Three other genes implicated for ARVC, plakoglobin (Naxos disease), desmoplakin (ARVC8) and plakophilin (ARVC9) have prompted the speculation that ARVC is primarily a disease of desmosomes. But identification of TGFb-3 for ARVC1 and the role of all these three genes (plakoglobin, desmoplakin and plakophilin) in cardiac morphogenesis indicate some kind of signal-transducing pathway disruption in the condition. The finding that ARVC as a milder form of Uhl's anomaly indicates similar ontogeny for the condition. Further, discovery of apoptotic cells in the autopsy of the right ventricular myocardium of ARVC patients does indicate a common pathway for different types of ARVCs, which is more specific for the right ventricular myocardium involving desmosomal plaque proteins, growth factors and Ca 2+ receptors.

Research paper thumbnail of Novel mutations in beta-myosin heavy chain, actin and troponin-I genes associated with dilated cardiomyopathy in Indian population

Journal of Genetics, 2009

Research paper thumbnail of Epidemiology and genetics of dilated cardiomyopathy in the Indian context

Indian Journal of Medical Sciences, 2009

BACKGROUND: Dilated cardiomyopathy (DCM) still remains to be a poorly understood and less analyze... more BACKGROUND: Dilated cardiomyopathy (DCM) still remains to be a poorly understood and less analyzed group of cardiac-muscle disorders when compared to hypertrophic cardiomyopathy (HCM). Also, the vast clinical heterogeneity among the patients has rendered the small and isolated kindred studies less informative on the genetics and epidemiology of DCM. AIM OF THE STUDY: The study aimed at understanding the epidemiology and genetics of DCMs in the Indian context. MATERIALS AND METHODS/ STATISTICAL ANALYSIS: One hundred seven DCM patients and 105 healthy individuals were included in the study for epidemiological and genetic risk factor identification and to fit the possible mode of inheritance. Single's ascertainment methodology for segregation analysis and Penrose frequency estimates were followed to evaluate for the role of specific epidemiological factors in the disease etiology. Chi-square analysis was carried out to interpret the results statistically. RESULTS AND CONCLUSION: Our study suggests that epidemiological factors like gender, age at onset and vegetarian diet in conjunction with sarcomere gene mutations may play a role in the disease expression. Similarly, segregation analysis for the possible mode of inheritance showed a deviation from the autosomal dominant mode of inheritance, strengthening the underlying genetic heterogeneity of DCM.

Research paper thumbnail of © Kamla-Raj 2009 Int J Hum Genet, 9(3-4): 263-267 (2009) Pro and Anti-Oxidants in Cardiomyopathy

Free radicals play an essential role in maintaining the physiological condition of the body and o... more Free radicals play an essential role in maintaining the physiological condition of the body and oxidative stress is a result of an imbalance between free radicals and protective endogenous antioxidants, mostly associated with inflammatory disorders. Since cardiomyopathy is also an inflammatory disorder, the role of pro and anti oxidants is executed. Overall 180 cases (83 HCM and 97 DCM cases) and 100 healthy volunteers were included in the study. 5ml of venous blood samples were collected for the analysis of Malondialdehyde, Nitric oxide and Ceruloplasmin levels. MDA was found to be high in HCM whereas NO and Cp levels were high in DCM. Based on the findings it can be concluded that, Hypertrophic cardiomyopathy can results due to an imbalance in pro-oxidants while Dilated cardiomyopathy is an end result of oxidative stress. Hence the pro-oxidants MDA and NO, and antioxidant ceruloplasmin levels, may serve as prognostic indicators in hypertrophic and dilated cardiomyopathy, with fail...

Research paper thumbnail of miRNA regulation during cardiac development and remodeling in cardiomyopathy

miRNAs have been found to play a major role in cardiomyopathy, a heart muscle disorder characteri... more 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.

Research paper thumbnail of 5HTT Promoter Polymorphism in Idiopathic Pulmonary Arterial Hypertension

INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2011

Corneal dystrophies are defined as a group of inherited corneal disorders characterized by opacif... more Corneal dystrophies are defined as a group of inherited corneal disorders characterized by opacification of the cornea. Initial classification of corneal dystrophies was based on the layer of cornea involved but with the advent of better technology, a larger picture has evolved that includes both phenotypic and genotypic variants. With the evolving knowledge, a revised classification has been proposed by the International Committee for Classification of Corneal Dystrophies (IC3D). This classification has taken into account the clinical, histologic and genetic basis of the disease, integrating them into one. Our understanding of corneal dystrophies has reached new heights with mutations identified in at least 14 genes. Even though there has been a vast addition of information to the database, we still come across new variants which may seem enigmatic phenotypically. With the additional new information refining the molecular basis, there is a need to explore further the underlying molecular pathology so as to enable the possibility of better treatment modalities to the affected patients and their families. In view of the recent advances, we hereby review the dystrophies with an aim to provide updated information on the clinical and molecular aspects of corneal dystrophies which will aid in their differential diagnosis and management.

Research paper thumbnail of Superoxide Dismutase–A Genetic Marker in Cardiomyopathies

INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2003

Cardiomyopathies are a heterogeneous group of heart muscle disorders responsible for a great deal... more Cardiomyopathies are a heterogeneous group of heart muscle disorders responsible for a great deal of morbidity and mortality. Dilated, hypertrophic and restrictive are the three major categories of cardiomyopathies. Since reactive oxygen species has been implicated in wide range of genetic disorders and the role of antioxidant like superoxide dismutase as a scavenger has been highlighted, the present study envisages on identifying the specific electromorphic association of superoxide dismutase with cardiomyopathies and to delineate the genetic heterogeneity based on specific alleles at risk. Phenotyping was carried out on 8% PAGE of the red cell membrane samples following Davies (1964) and Beauchamp's (1975) protocols. Blood samples from 62 dilated cardiomyopathy, 80 hypertrophic cardiomyopathy and 86 healthy individuals were collected from CARE Hospitals and voluntary blood donor camps, Hyderabad. Significant association of homozygous SOD A*1 (χ 2 = 7.58) alleles with dilated cardiomyopathy and heterozygous SOD A*2-1 (χ 2 = 5.89) alleles with hypertrophic cardiomyopathy was observed, resulting in significant deviation of allelic frequency in cardiomyopathy group compared to the control group highlighting that individuals carrying SOD A*1 (χ 2 = 7.588) and SOD A*2-1 (χ 2 = 5.89) alleles may be at a greater risk for dilated and hypertrophic cardiomyopathy respectively. Thus SOD as a genetic marker may help in risk prediction and in delineating genetic heterogeneity of the condition and the role of superoxide dismutase with specific electromorphic association in influencing endogenous nitric oxide production and energy pathways by altering the structure and function of the cell membranes is discussed.

Research paper thumbnail of Pro and Anti-Oxidants in Cardiomyopathy

INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2009

Research paper thumbnail of Genetic Markers in Idiopathic Pulmonary Arterial Hypertension (IPAH)

INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2009

Idiopathic pulmonary arterial hypertension (IPAH) is a rare disorder with abnormally raised pulmo... more Idiopathic pulmonary arterial hypertension (IPAH) is a rare disorder with abnormally raised pulmonary arterial pressure. In IPAH, the trigger of the endothelial injury may result from oxidative stress, hypoxia, shear stress, inflammation in conjunction with genetic susceptibility. These epigenetic factors may have an influence on cell growth, differentiation and normal homeostatic functions of the endothelium, by altering endothelial permeability, production of growth factors and coagulation factors. Lung inflammation can lead to increased levels of oxidants that may also contribute to the development of IPAH. When the production of ROS exceeds, the capacity of the cell to detoxify them decreases and the resulting oxidative stress may be harmful to the integrity of biological tissue. Since in IPAH there is disruption of pulmonary artery vasculature, the generation of free radicals may further aggravate tissue injury and in view of its role in defensive mechanism, qualitative variation of SOD, CAT, AAT in IPAH is investigated in the present study to correlate specific electromorphic associations in its etiopathogenesis. In conclusion the present study revealed that Oxidative stress pathway (ROS/RNS) and inflammatory components may act as modifiers in pathogenicity of IPAH.

Research paper thumbnail of Association of Polymorphic Antioxidant Enzymes with Dilated Cardiomyopathy

INTERNATIONAL JOURNAL OF HUMAN GENETICS, 2009

Despite considerable public awareness and technological advances that foster early diagnosis and ... more Despite considerable public awareness and technological advances that foster early diagnosis and aggressive therapeutic interventions, heart failure, which results as a final outcome from an underlying cardiovascular disorder remains a critical and an unsolved problem. Among the various cardiomyopathies, Dilated cardiomyopathy with an obscure etiology is known to be the leading cause of heart failure and sudden cardiac death among young adults and children. Studies related to the molecular basis of the condition have implicated oxidative stress pathways, apart from primary disease causing sarcomeric, cytoskeletal and mitochondrial gene mutations in the disease onset. The present study aims to evaluate the role of oxidative stress markers in 97 DCM patients and 105 control individuals to identify specific electromorphic association of superoxide dismutase, catalase and alpha-1-antitrypsin with the disease. Our study has revealed an association of SODA2, catalase HPII and AAT 'M' and 'Z' alleles with DCM, thereby resulting in inefficient scavenging of the free radicals, which may confer decreased protection against oxidative stress induced tissue injury in the disease pathogenesis. The involvement of SOD and AAT in apoptotic pathway and as immunomodulators is also emphasized.

Research paper thumbnail of Variants of PGIS and PPARγ in Idiopathic Pulmonary Arterial Hypertension

International Journal of Genomic Medicine, 2015

J o u rn al of C li n ic al & M e d ic a l G enom ic s

Research paper thumbnail of Implication of hsp70 gene polymorphisms in Arrhythmogenic right ventricular cardiomyopathy/dysplasia

JOURNAL OF HEART AND CARDIOLOGY, 2015

Introduction: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized... more Introduction: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by initial fibrofatty replacement of the right ventricle. Mutations in the Desmosomal and non desmosomal apart from modifier genes are known to be involved in the pathogenesis of the ARVC/D. One such modifier gene identified is HSP70 which plays an important role in cardio-protection. The present study investigates the role of Hsp70 polymorphisms in ARVC/D disease severity. Methods: Analysis of 100 control samples and 33 ARVC/D patients for 3 polymorphic loci was carried out by PCR-RFLP. Statistical analysis was carried out by SNPSTAT and haploview to analyze the genotypic data generated. Results: Our study revealed a statistically significant association of GC genotype (HSP70-1 +190G/C) [OR 2.93,95%CI 1.08-8.00, p=0.035] and TC genotype (HSP70-hom +2437T/C) [OR 2.04, 95% CI 1.01-4.55, p=0.045] with risk to develop ARVC/D. The haplotype frequency of CGT was also found to be higher in patients compared to controls, strengthening the synergistic effect of HSP70 family in ARVC/D. Conclusions: The present investigation revealed the importance of HSP70 polymorphisms in the pathogenesis of the ARVC/D. The results highlight a modifier role of HSP70 polymorphisms in ARVC/D etiopathogenesis, as the synergistic action of these polymorphisms may inhibit the HSP70 protein to perform its regular role, which in turn may trigger inflammation and apoptosis, hence the muscle tissue may be replaced by fibrofatty tissue.

Research paper thumbnail of Endothelin-1 and endothelial nitric oxide polymorphisms in idiopathic pulmonary arterial hypertension

International journal of molecular epidemiology and genetics, Jan 15, 2010

Idiopathic Pulmonary arterial hypertension (IPAH) is a debilitating disease associated with very ... more Idiopathic Pulmonary arterial hypertension (IPAH) is a debilitating disease associated with very poor prognosis. The disease is characterised by endothelial dysfunction, smooth muscle proliferation and insitu thrombosis in the pulmonary artery, eventually leading to right ventricular failure. Two of the key endothelial mediators implicated in the pathogenesis of IPAH are endothelin-1 (EDN1) and nitric oxide (NO). EDN1 is a potent endogenous vasoconstrictor whereas NO is a vasodilator. In the present study screening of the EDN1 gene (EDN1) and NOS3 polymorphisms was taken up, to evaluate their association with IPAH. A significant association of EDN1 3A/4A polymorphism (+138 A; rs10478694) (OR-3.485; CI-1.254, 9.999; p=0.013) and EDN1 Lys198Asn polymorphism (G/T, rs5370) (OR-3.378, CI-1.104, 10.582; p=0.03) with IPAH was observed. Our results indicate that EDN1 polymorphisms in interaction with other genetic markers may play a significant role in individual's susceptibility to the...

Research paper thumbnail of The genetic bases of uterine fibroids; a review

Journal of reproduction & infertility, 2011

Uterine leiomyomas/fibroids are the most common pelvic tumors of the female genital tract. The in... more 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% karyo-typically 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 c...

Research paper thumbnail of Genetic variations of α-cardiac actin and cardiac muscle LIM protein in hypertrophic cardiomyopathy in South India

Experimental and clinical cardiology, 2012

Hypertrophic cardiomyopathy (HCM) is a disease of the heart muscle, with an autosomal dominant mo... more Hypertrophic cardiomyopathy (HCM) is a disease of the heart muscle, with an autosomal dominant mode of inheritance. It is also known as the 'disease of the sarcomere', and is a major cause of morbidity and mortality worldwide. Mutations in the sarcomeric genes have been largely implicated in the manifestation of HCM. Modifier genes and environmental factors, along with causative mutation, add to the cumulative effect of the disease. In the present study, the role of the cardiac actin gene and the cardiac muscle LIM protein as contributors to HCM - through genetic variation - has been elucidated by screening the entire coding region in 100 control and 100 HCM subjects through polymerase chain reaction-based single-strand conformation polymorphism analysis and direct sequencing. The authors could not find any novel or reported exonic variations in any of the genes in the studied population; however, intronic variations were revealed in the cardiac actin gene through direct seq...

Research paper thumbnail of Modifier Genes in Hypertrophic Cardiomyopathy Patients of South Indian Cohort

International Journal of Genetics and Genomics, 2014

Hypertrophic cardiomyopathy is an autosomal dominant disorder, characterized by thickening of the... more Hypertrophic cardiomyopathy is an autosomal dominant disorder, characterized by thickening of the myocardium with a variable clinical course. Mutations in 14 sarcomeric genes have been implicated resulting in phenotypic and genotypic heterogeneity. The phenotypic expression of HCM is not only determined by the sarcomeric gene mutations but the genetic predilection of an individual also account for the inter-individual variability and genes with such functional variants that affect phenotypic expression are referred to as Modifier genes. Hence genetic variants of Angiotensin converting enzyme (ACE-2), Tumor necrosis factor-alpha (TNF-α) and Heat shock protein-70 (HSP70) genes have been considered in the present study to understand their role as modifiers of HCM. The study was carried out by Genotyping of 100 HCM and 100 controls by Polymerase chain reaction based restriction fragment length polymorphism analysis. The present study revealed a significant association of the HSP70-1 and HSP70-2 polymorphisms while ACE-2 and TNF-α genes were found to be statistically insignificant. However patients with the rare/variant genotypes were observed to have stronger clinical manifestations and echocardiographic parameters. This was further confirmed by Linkage disquillibrium analysis wherein individuals with the haplotypes GCGC and GCGT seemed to have increased susceptibility to HCM. The MDR analysis revealed a synergistic interaction of TNF-α with ACE-2 and HSP70 polymorphisms indicating their modifying effect in the presence of other environmental factors. Hence the present study emphasized the role of ACE-2, TNF-α and HSP70 polymorphisms as modifiers of the phenotypic expression in conjunction with other sarcoemric mutations and single nucleotide variations.

Research paper thumbnail of A Novel Arginine to Tryptophan (R144W) Mutation in Troponin T (cTnT) Gene in an Indian Multigenerational Family with Dilated Cardiomyopathy (FDCM)

PLoS ONE, 2014

Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in s... more Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in sarcomeric protein genes have been associated with this disease. Our aim in the present study is to investigate the genetic variations in Troponin T (cTnT) gene and its association with dilated cardiomyopathy (DCM) in south-Indian patients. Analyses of all the exons and exon-intron boundaries of cTnT in 147 DCM and in 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL; of which, polymorphic SNPs were compared with the HapMap population data. Interestingly, a novel R144W mutation, that substitutes polar-neutral tryptophan for a highly conserved basic arginine in cTnT, altering the charge drastically, was identified in a DCM, with a family history of sudden-cardiac death (SCD). This mutation was found within the tropomyosin (TPM1) binding domain, and was evolutionarily conserved across species, therefore it is expected to have a significant impact on the structure and function of the protein. Family studies had revealed that the R144W is co-segregating with disease in the family as an autosomal dominant trait, but it was completely absent in 207 healthy controls and in 162 previously studied HCM patients. Further screening of the proband and three of his family members (positive for R144W mutant) with eight other genes b-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3, did not reveal any disease causing mutation, proposing the absence of compound heterozygosity. Therefore, we strongly suggest that the novel R144W unique/private mutant identified in this study is associated with FDCM. This is furthermore signifying the unique genetic architecture of Indian population.

Research paper thumbnail of Haplotypes of NOS3 Gene Polymorphisms in Dilated Cardiomyopathy

PLoS ONE, 2013

Dilated Cardiomyopathy (DCM) is characterized by systolic dysfunction, followed by heart failure ... more 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.

Research paper thumbnail of A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia

Research paper thumbnail of Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

Journal of Human Genetics, 2003

The disease is characterized by extreme clinical and morphological heterogeneity, ranging from be... more The disease is characterized by extreme clinical and morphological heterogeneity, ranging from benign to severe, and is further complicated by a variable age of presentation.

Research paper thumbnail of Etiopathogenesis of arrhythmogenic right ventricular cardiomyopathy

Journal of Human Genetics, 2005

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterised by progressive fibrofatty... more Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterised by progressive fibrofatty replacement of right ventricular myocardium. Earlier studies described ARVC as non-inflammatory, non-coronary disorder associated with arrhythmias, heart failure and sudden death due to functional exclusion of the right ventricle. Molecular genetic studies have identified nine different loci associated with ARVC; accordingly each locus is implicated for each type of ARVC (ARVC1-ARVC9). So far five genes have been identified as containing pathogenic mutations for ARVC. Though mutations in each of the gene/s indicate disruption of different pathways leading to the condition, the exact pathogenesis of the condition is still obscure. This review tries to understand the pathogenesis of the condition by examining the individual proteins implicated and relate them to the pathways that could play a role in the aetiology of the condition. Cardiac ryanodine receptor (RYR-2), which regulates intra-cellular Ca 2+ concentration by releasing Ca 2+ reserves from the sarcoplasmic reticulum (SR), was the first gene for ARVC. The mutation in this gene is believed to disrupt coupled gating of RYR-2, causing after-depolarisation, leading to arrhythmias followed by structural changes due to altered intra-cellular Ca 2+ levels. Three other genes implicated for ARVC, plakoglobin (Naxos disease), desmoplakin (ARVC8) and plakophilin (ARVC9) have prompted the speculation that ARVC is primarily a disease of desmosomes. But identification of TGFb-3 for ARVC1 and the role of all these three genes (plakoglobin, desmoplakin and plakophilin) in cardiac morphogenesis indicate some kind of signal-transducing pathway disruption in the condition. The finding that ARVC as a milder form of Uhl's anomaly indicates similar ontogeny for the condition. Further, discovery of apoptotic cells in the autopsy of the right ventricular myocardium of ARVC patients does indicate a common pathway for different types of ARVCs, which is more specific for the right ventricular myocardium involving desmosomal plaque proteins, growth factors and Ca 2+ receptors.

Research paper thumbnail of Novel mutations in beta-myosin heavy chain, actin and troponin-I genes associated with dilated cardiomyopathy in Indian population

Journal of Genetics, 2009

Research paper thumbnail of Epidemiology and genetics of dilated cardiomyopathy in the Indian context

Indian Journal of Medical Sciences, 2009

BACKGROUND: Dilated cardiomyopathy (DCM) still remains to be a poorly understood and less analyze... more BACKGROUND: Dilated cardiomyopathy (DCM) still remains to be a poorly understood and less analyzed group of cardiac-muscle disorders when compared to hypertrophic cardiomyopathy (HCM). Also, the vast clinical heterogeneity among the patients has rendered the small and isolated kindred studies less informative on the genetics and epidemiology of DCM. AIM OF THE STUDY: The study aimed at understanding the epidemiology and genetics of DCMs in the Indian context. MATERIALS AND METHODS/ STATISTICAL ANALYSIS: One hundred seven DCM patients and 105 healthy individuals were included in the study for epidemiological and genetic risk factor identification and to fit the possible mode of inheritance. Single's ascertainment methodology for segregation analysis and Penrose frequency estimates were followed to evaluate for the role of specific epidemiological factors in the disease etiology. Chi-square analysis was carried out to interpret the results statistically. RESULTS AND CONCLUSION: Our study suggests that epidemiological factors like gender, age at onset and vegetarian diet in conjunction with sarcomere gene mutations may play a role in the disease expression. Similarly, segregation analysis for the possible mode of inheritance showed a deviation from the autosomal dominant mode of inheritance, strengthening the underlying genetic heterogeneity of DCM.