Anita Nadkarni - Academia.edu (original) (raw)
Papers by Anita Nadkarni
Blood Cells Molecules and Diseases, Apr 1, 2014
Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of... more Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease, an effect mediated by its exclusion from the sickle hemoglobin polymer. Fetal hemoglobin genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Some patients with sickle cell disease have exceptionally high levels of HbF that are associated with the Senegal and Saudi-Indian haplotype of the HBBlike gene cluster; some patients with different haplotypes can have similarly high HbF. In these patients, high HbF is associated with generally milder but not asymptomatic disease. Studying these persons might provide additional insights into HbF gene regulation. HbF appears to benefit some complications of disease more than others. This might be related to the premature destruction of erythrocytes that do not contain HbF, even though the total HbF concentration is high. Recent insights into HbF regulation have spurred new efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of HbF inducers. (Blood. 2011;118(1):19-27) HbF and the retardation of HbS polymerization HbF is composed of 2 ␣-globin polypeptide chains and 2 ␥-globin chains. The ␥-globin chains are encoded by 2 nearly identical genes (HBG2 and HBG1) within the -globin gene-like cluster on chromosome 11p that differ by a glycine or alanine residue at
Expert Review of Hematology, Jul 3, 2023
Scientific Reports, Jan 7, 2023
is found to be beneficial in sickle cell anaemia (SCA) patients, due to its ability to increase f... more is found to be beneficial in sickle cell anaemia (SCA) patients, due to its ability to increase foetal haemoglobin (HbF), however, patients show a variable response. Differences in HbF levels are attributed to many factors; but, the role of miRNA in HbF regulation is sparsely investigated. In this study, we evaluated the effect of miRNA expression on HbF induction in relation to hydroxyurea therapy in 30 normal controls, 30 SCA patients at baseline, 20 patients after 3 and 6 months of hydroxyurea (HU) therapy. HbF levels were measured by HPLC. Total RNA and miRNA were extracted from CD71 + erythroid cells and the expression was determined using Taqman probes. The mean HbF level increased 7.54 ± 2.44 fold, after 3 months of HU therapy. After the HU therapy 8 miRNAs were significantly up-regulated while 2 were down-regulated. The increase in miR-210, miR16-1, and miR-29a expression and decrease in miR-96 expression were strongly associated with the HU mediated HbF induction. Post HU therapy, decreased miR-96 expression negatively correlate with HbF and γ-globin gene while increased expression of miR-210, miR-16-1 and miR-29a post HU therapy positively corelate with HbF and γ-globin gene. Thus, suggest that miR-210, miR-16-1 and miR-29a are positive regulator of γ-globin gene and miR-96 is negative regulator of γ-globin gene. The study suggests the role of miR-210, miR16-1, miR-29a, and miR-96 in γ-globin gene regulation leading to HbF induction. Identification of the relevant protein targets might be useful for understanding the HU mediated HbF induction. Sickle cell anaemia (SCA) is a monogenic disorder caused by an amino acid change from Glutamic acid to Valine in the β-globin chain at codon 6 position. This change leads to the formation of abnormal haemoglobin (Sickle haemoglobin or HbS) with altered physiological properties. Under a deoxygenated state, the non-polar hydrophobic Valine residue is exposed on the surface of the βS chain, triggering intermolecular interactions and polymerization of haemoglobin. The outcome is deformities in the RBC shape, from normal biconcave to rigid sickle shape which while flowing through the bloodstream, aggregate and blocks the small capillaries triggering vaso-occlusive crisis 1. The prevalence of SCA is predominant in tribal population of India. Majority of tribal population of India accounts 83% of total population. The SCA trait frequency among the tribal population range from 1 to 35%. Since most of the tribal population are inhabited in rural areas, government and non-government organizations are involved in bridging the gap between patients and health care facilities. Severity of SCD in India is not uniformly mild despite high fetal hemoglobin levels. The benefits of comprehensive care and hydroxyurea therapy to patients are achieved through organizations 2. The most effective treatment for SCA is the induction of foetal haemoglobin (HbF; α2γ2) which along with its mixed hybrid tetramer (α2βSγ) inhibits sickle haemoglobin polymerization, thus circumventing the cellular damage evoked by the deoxy-sickle haemoglobin 3. Hydroxyurea, a myelosuppressive agent, is the only effective drug that has proven to be effective for treating SCA, through HbF induction. However, HbF induction by hydroxyurea is highly variable among patients, and its mechanism of HbF reactivation remains unclear. Nonetheless, three main molecular pathways for HU-mediated response in increase HbF have been reported earlier: (i) Regulation of gene expression by epigenetic modifications (ii) Signaling pathways and (iii) post-transcriptional pathways with regulation by Small non-coding RNA oligonucleotides (miRNA) 4 .
PubMed, Apr 12, 2023
Background: Sickle cell disease (SCD) is one of the most common hemoglobinopathy disorders and is... more Background: Sickle cell disease (SCD) is one of the most common hemoglobinopathy disorders and is widely prevalent in India, especially in the tribal population. SCD patients are prone to develop recurrent respiratory infections and related complications owing to the microvascular occlusion and impaired immunological response. Objectives: We aimed to determine the prevalence and impact of COVID-19 in SCD patients from India. Methodology: We conducted a cross-sectional study in Chandrapur district of Maharashtra, India, between August and October 2021. After taking informed consent, details of 300 SCD patients' demographic data, history of COVID-19 testing, infection, symptoms related to COVID-19 in the past 1 year, hospitalization, complications, mortality, COVID-19 vaccination, and side effects were recorded. Results: We found that 93 (31%) of SCD patients had influenza-like symptoms during the COVID-19 pandemic with symptoms of fever (81.72%), cough (35.48%), sore throat (18.27%), headache (15.05%), and breathlessness (7.52%). A total of 13 (4.33%) SCD among 300 SCD were tested as COVID positive. Majority of them were mild cases and the 1st dose of COVID-19 vaccine was received by 47 (29.37%) of SCD patients and 10 (6.02%) of the patient had received second dose of vaccine. Conclusion: Low incidence of COVID-19 and milder disease spectrum in our study cohort suggests that there is no increased risk of COVID-19 mortality and morbidity in SCD patients compared to general population. However, the reason for low COVID vaccination in our study could be due to the fear of complications of COVID vaccine.
International Journal of Laboratory Hematology, 2017
P50 values, as with patients in this study, it is important to eliminate the possibility of Hb va... more P50 values, as with patients in this study, it is important to eliminate the possibility of Hb variants by sequencing the globin genes, which confirmed 6 positive cases on the registry.
Indian Journal of Medical Research, 2015
Journal of Hematopathology, Sep 14, 2022
International Journal of Laboratory Hematology, Jul 30, 2015
ABSTRACT The term thalassemia intermedia describe a form of thalassemia of intermediate severity,... more ABSTRACT The term thalassemia intermedia describe a form of thalassemia of intermediate severity, between the major transfusion-dependent forms of the disease and the symptomless carrier states. The phenotypic diversity of β-thalassemia results from its underlying genetic diversity. The wide clinical variability of these conditions leads to major difficulties in their management. The molecular basis of thalassemia intermedia is very heterogeneous. The clinical and hematological course of β-thalassemia intermedia is influenced by a number of genetic factors. The main aim of the study was to evaluate the effect of globin and nonglobin genetic modifiers on clinical severity of the disease. The study group consisted of 66 homozygous patients with β-thalassemia [40 transfusion-dependent thalassemia (TDT), 26 nontransfusion-dependent thalassemia (NTDT)]. Hepatosplenomegaly was pronounced in the NTDT group. The presence of associated α-thalassemia was significantly higher in untransfused patients (P < 0.05). The milder β-thalassemia mutations, such as Cap site +1 (A→C), -88 (C→T), and -87 (C→G), were observed mainly in the NTDT group (9.61%) as against patients with TDT (1.25%). The cis-DNA haplotypes, motifs, or polymorphisms around the gamma-globin genes [(AT)x (T)y motif (38.4%), XmnI (76.92%)and the Aγ-δ intergenic region haplotype T (73.07%) and Pre Gγ globin gene haplotype TAG (46.15%)] contributed significantly in amelioration of the disease severity. Our study emphasizes the complexity of genetic interactions that underlie the phenotype of β-thalassemia and highlights the importance of epistatic factors and the regulation of HbF production in β-thalassemia syndromes. © 2015 John Wiley & Sons Ltd.
Annals of Human Genetics, Mar 31, 2017
The Kruppel-like factor 1 (KLF1) gene is an essential transcription factor that is required for t... more The Kruppel-like factor 1 (KLF1) gene is an essential transcription factor that is required for the proper maturation of the erythroid cells. Recent studies have reported that KLF1 variations are associated with increased fetal hemoglobin (HbF) levels. Here we report a novel KLF1 gene variation codon 211 A→G (c.632 A&amp;gt;G) in a family who was referred for hemoglobinopathy screening. Both parents were classical β-thalassemia trait (mother: HbA2 4.1%, HbF 8.6%; father: HbA2 5.5%, HbF 0.6%) codon 15 G→A heterozygous, and the child was β-thalassemia homozygous. Because the mother showed a high HbF level, the genetic determinants for raised HbF were screened. We detected a novel KLF1 gene variant in the mother and the child in the heterozygous state. The co-inheritance of this novel KLF1 variant might have increased the HbF levels in the mother and may have ameliorated the clinical manifestations of the 6-year-old untransfused β-thalassemia homozygous child. Identification of KLF1 gene variants may act as a novel target for increasing HbF levels in patients with β-hemoglobinopathies.
Scandinavian Journal of Rheumatology, Sep 3, 2015
This is a repository copy of Association between the angiotensin-converting enzyme gene insertion... more This is a repository copy of Association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and susceptibility to systemic lupus erythematosus in an Indian population..
Blood Cells Molecules and Diseases, May 1, 2022
INTRODUCTION β-thalassemia is an autosomal recessive disorder of hemoglobin (Hb) production cause... more INTRODUCTION β-thalassemia is an autosomal recessive disorder of hemoglobin (Hb) production caused by a reduced amount (β +) or absence (β 0) of β-globin chain synthesis resulting in a relative excess of unbound α-globin chains that precipitate in erythroid precursors leading to ineffective erythropoiesis. [1] The pathogenesis of β-thalassemia is a complex, multisystem process with different genetic and epigenetic markers influencing the phenotype of the disease. [2] An estimated 1.5% of the global population are carriers of β-thalassemia, with about 60,000 symptomatic individuals born annually. [3] In India, the carrier rate for β-thalassemia varies from 1% to 17% [4,5] among certain high-risk communities with an average frequency of 3-4% [6,7] and an estimated birth of 8000-10,000 babies with severe forms
Annals of Hematology, Apr 20, 2016
An association between maternal age and offspring LTL and the interaction with BD was observed. I... more An association between maternal age and offspring LTL and the interaction with BD was observed. It could be speculated that an influence of oxidative stress during first pregnancy, changes in mitochondrial DNA or even other parent-specific imprinting mechanism, such as DNA methylation, relevant to the neurodevelopment of the brain. To our knowledge, this is the first study evaluating association of maternal age and telomere length in the offspring of families with several members affected by BD. Additional studies are needed to confirm these preliminary findings.
Mutation Research-reviews in Mutation Research, Jul 1, 2021
There is inconsistency in the exact definition of diagnostic levels of HbA2 for β thalassemia tra... more There is inconsistency in the exact definition of diagnostic levels of HbA2 for β thalassemia trait. While many laboratories consider HbA2 ≥4.0 % diagnostic, still others consider HbA2 ≥3.3 % or HbA2 ≥3.5 % as the cut-off for establishing β thalassemia carrier diagnosis. This is because, over the years, studies have described β thalassemia carriers showing HbA2 levels that lie above the normal range of HbA2 but below the typical carrier range of β thalassemia. These, "borderline HbA2 levels", though not detrimental to health, are significant in β thalassemia carrier diagnosis because they can lead to misinterpretation of results. In this review, we have evaluated the prevalence of borderline HbA2 levels and discussed the causes of borderline HbA2 values. We have also compiled an extensive catalogue of β globin gene defects associated with borderline HbA2 levels and have discussed strategies to avoid misdiagnosing borderline HbA2 β thalassemia carriers. Our analysis of studies that have delineated the cause of borderline HbA2 levels in different populations shows that 35.4 % [626/1766] of all individuals with borderline HbA2 levels carry a molecular defect. Among the positive samples, 17 % [299/1766] show β globin gene defects, 7.7 % [137/1766] show α thalassemia defects, 2.7 % [49/1766] show KLF1 gene mutations, 2.3 % [41/1766] show the co-inheritance of β and α thalassemia, 2.0 % [37/1766] show the co-inheritance of β and δ thalassemia and 1.8 % [32/1766] show α globin gene triplication. It appears that a comprehensive molecular work up of the β globin gene is the only definite method to detect borderline HbA2 β thalassemia carriers, especially in populations with a high prevalence of the disease. The presence of associated genetic or acquired determinants may subsequently be assessed to identify the cause of borderline HbA2.
Clinical Genetics
MicroRNAs are the major class of small non-coding RNAs, evolutionary conserved posttranscriptiona... more MicroRNAs are the major class of small non-coding RNAs, evolutionary conserved posttranscriptional regulators of gene expression. Since their discovery in 1993, they have been implicated as master regulators in numerous cellular processes. MicroRNA (miRNA)s regulate gene expression by attenuation and/or mRNA degradation and are commonly associated with cell development, differentiation, and homeostasis. Extensive research in past two decades has provided new insights into the potential implications of miRNA in the onset, progression, and therapeutic nature of miRNAs in disease manifestation. Owing to the novel discoveries, "miRNAs" would probably pave a new direction in therapeutic research. However, "micro" in length miRNAs have attracted considerable attention in numerous other fields. Understanding the functionality of miRNAs, in this review article, we discussed the mechanistic role of miRNAs in human diseases and have outlined most of the recent published work in clinical therapeutics. We have constructed different network models for miRNA and its targets which made us understand their interrelationship and association with diseases. Future research would surely overcome challenges and would introduce new strategies for the utility of miRNAs in a broader setting.
Indian Journal of Pathology and Microbiology
Hemoglobin, 2021
Abstract The β-thalassemias and sickle cell disorders pose a considerable health burden in India.... more Abstract The β-thalassemias and sickle cell disorders pose a considerable health burden in India. Of the more than 10,000 annual births of children with a severe hemoglobinopathy, only around 10.0% are managed optimally. Thus, genetic counseling and prenatal diagnosis (PND) is a valid option for a large and diverse country. Our center was one of the first to initiate PND and we present our experience over 30 years to evaluate the impact of awareness in changing the trends of PND of hemoglobinopathies. Both second and first-trimester diagnoses were undertaken by fetoscopy/cordocentesis and globin biosynthesis/high-performance liquid chromatography (HPLC) analysis of fetal blood and chorionic villus sampling (CVS) and DNA analysis. Over 30 years, 3478 couples (first trimester: 2475; second trimester: 1003) from all over India were offered PND. The number of couples coming in the first trimester increased significantly over each decade and couples coming prospectively increased from 2.5 to 18.4%. A cost-effective stepwise approach was used for molecular analysis. Eight hundred and one fetuses (23.0%) were affected and all except three couples opted for termination of these pregnancies. Genetic counseling and PND is the only way to reduce the burden of disease. With awareness, there was a shift from second trimester to first trimester PND over each decade, with an increasing number of couples coming during the first pregnancy. There are only 15 to 20 centers in India offering PND. We have compared our study with other reports on PND from different regions in India.
![Research paper thumbnail of Original Communication - Detection of two rare β-thalassemia mutations [-90 (C → T) and CD 26 (C →T)] among Indians](https://attachments.academia-assets.com/111020339/thumbnails/1.jpg)
](Medknow Publications on behalf of Indian Society of Human Genetics, Dec 31, 2005
BACKGROUND : β-Thalassemia (β-thal) is present in practically every caste group in Indians. Molec... more BACKGROUND : β-Thalassemia (β-thal) is present in practically every caste group in Indians. Molecular characterization of β-thal in these groups has revealed an extremely heterogeneous picture. AIM: To identify all the mutations and to detect the novel mutations using a versatile mutation detection technique. MATERIALS AND METHODS: Denaturing gradient gel electrophoresis (DGGE) has been established to scan the entire β-globin gene to localize the mutation followed by DNA sequencing for characterization. The DNA samples from two families referred to us either for prenatal diagnosis or for DNA studies were studied. RESULTS: Atypical DGGE patterns in fragments B & A indicating the presence of the mutation, have been detected in both the families. DNA sequencing revealed two rare patterns fragments with patterns in fragments β-thal mutations [CD 26 (C→T) and-90 (C→T)]. CONCLUSION: DGGE is a useful mutation detection technique to identify β-thal mutations among the heterogeneous Indian population.
Blood Cells Molecules and Diseases, Apr 1, 2014
Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of... more Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease, an effect mediated by its exclusion from the sickle hemoglobin polymer. Fetal hemoglobin genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Some patients with sickle cell disease have exceptionally high levels of HbF that are associated with the Senegal and Saudi-Indian haplotype of the HBBlike gene cluster; some patients with different haplotypes can have similarly high HbF. In these patients, high HbF is associated with generally milder but not asymptomatic disease. Studying these persons might provide additional insights into HbF gene regulation. HbF appears to benefit some complications of disease more than others. This might be related to the premature destruction of erythrocytes that do not contain HbF, even though the total HbF concentration is high. Recent insights into HbF regulation have spurred new efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of HbF inducers. (Blood. 2011;118(1):19-27) HbF and the retardation of HbS polymerization HbF is composed of 2 ␣-globin polypeptide chains and 2 ␥-globin chains. The ␥-globin chains are encoded by 2 nearly identical genes (HBG2 and HBG1) within the -globin gene-like cluster on chromosome 11p that differ by a glycine or alanine residue at
Expert Review of Hematology, Jul 3, 2023
Scientific Reports, Jan 7, 2023
is found to be beneficial in sickle cell anaemia (SCA) patients, due to its ability to increase f... more is found to be beneficial in sickle cell anaemia (SCA) patients, due to its ability to increase foetal haemoglobin (HbF), however, patients show a variable response. Differences in HbF levels are attributed to many factors; but, the role of miRNA in HbF regulation is sparsely investigated. In this study, we evaluated the effect of miRNA expression on HbF induction in relation to hydroxyurea therapy in 30 normal controls, 30 SCA patients at baseline, 20 patients after 3 and 6 months of hydroxyurea (HU) therapy. HbF levels were measured by HPLC. Total RNA and miRNA were extracted from CD71 + erythroid cells and the expression was determined using Taqman probes. The mean HbF level increased 7.54 ± 2.44 fold, after 3 months of HU therapy. After the HU therapy 8 miRNAs were significantly up-regulated while 2 were down-regulated. The increase in miR-210, miR16-1, and miR-29a expression and decrease in miR-96 expression were strongly associated with the HU mediated HbF induction. Post HU therapy, decreased miR-96 expression negatively correlate with HbF and γ-globin gene while increased expression of miR-210, miR-16-1 and miR-29a post HU therapy positively corelate with HbF and γ-globin gene. Thus, suggest that miR-210, miR-16-1 and miR-29a are positive regulator of γ-globin gene and miR-96 is negative regulator of γ-globin gene. The study suggests the role of miR-210, miR16-1, miR-29a, and miR-96 in γ-globin gene regulation leading to HbF induction. Identification of the relevant protein targets might be useful for understanding the HU mediated HbF induction. Sickle cell anaemia (SCA) is a monogenic disorder caused by an amino acid change from Glutamic acid to Valine in the β-globin chain at codon 6 position. This change leads to the formation of abnormal haemoglobin (Sickle haemoglobin or HbS) with altered physiological properties. Under a deoxygenated state, the non-polar hydrophobic Valine residue is exposed on the surface of the βS chain, triggering intermolecular interactions and polymerization of haemoglobin. The outcome is deformities in the RBC shape, from normal biconcave to rigid sickle shape which while flowing through the bloodstream, aggregate and blocks the small capillaries triggering vaso-occlusive crisis 1. The prevalence of SCA is predominant in tribal population of India. Majority of tribal population of India accounts 83% of total population. The SCA trait frequency among the tribal population range from 1 to 35%. Since most of the tribal population are inhabited in rural areas, government and non-government organizations are involved in bridging the gap between patients and health care facilities. Severity of SCD in India is not uniformly mild despite high fetal hemoglobin levels. The benefits of comprehensive care and hydroxyurea therapy to patients are achieved through organizations 2. The most effective treatment for SCA is the induction of foetal haemoglobin (HbF; α2γ2) which along with its mixed hybrid tetramer (α2βSγ) inhibits sickle haemoglobin polymerization, thus circumventing the cellular damage evoked by the deoxy-sickle haemoglobin 3. Hydroxyurea, a myelosuppressive agent, is the only effective drug that has proven to be effective for treating SCA, through HbF induction. However, HbF induction by hydroxyurea is highly variable among patients, and its mechanism of HbF reactivation remains unclear. Nonetheless, three main molecular pathways for HU-mediated response in increase HbF have been reported earlier: (i) Regulation of gene expression by epigenetic modifications (ii) Signaling pathways and (iii) post-transcriptional pathways with regulation by Small non-coding RNA oligonucleotides (miRNA) 4 .
PubMed, Apr 12, 2023
Background: Sickle cell disease (SCD) is one of the most common hemoglobinopathy disorders and is... more Background: Sickle cell disease (SCD) is one of the most common hemoglobinopathy disorders and is widely prevalent in India, especially in the tribal population. SCD patients are prone to develop recurrent respiratory infections and related complications owing to the microvascular occlusion and impaired immunological response. Objectives: We aimed to determine the prevalence and impact of COVID-19 in SCD patients from India. Methodology: We conducted a cross-sectional study in Chandrapur district of Maharashtra, India, between August and October 2021. After taking informed consent, details of 300 SCD patients' demographic data, history of COVID-19 testing, infection, symptoms related to COVID-19 in the past 1 year, hospitalization, complications, mortality, COVID-19 vaccination, and side effects were recorded. Results: We found that 93 (31%) of SCD patients had influenza-like symptoms during the COVID-19 pandemic with symptoms of fever (81.72%), cough (35.48%), sore throat (18.27%), headache (15.05%), and breathlessness (7.52%). A total of 13 (4.33%) SCD among 300 SCD were tested as COVID positive. Majority of them were mild cases and the 1st dose of COVID-19 vaccine was received by 47 (29.37%) of SCD patients and 10 (6.02%) of the patient had received second dose of vaccine. Conclusion: Low incidence of COVID-19 and milder disease spectrum in our study cohort suggests that there is no increased risk of COVID-19 mortality and morbidity in SCD patients compared to general population. However, the reason for low COVID vaccination in our study could be due to the fear of complications of COVID vaccine.
International Journal of Laboratory Hematology, 2017
P50 values, as with patients in this study, it is important to eliminate the possibility of Hb va... more P50 values, as with patients in this study, it is important to eliminate the possibility of Hb variants by sequencing the globin genes, which confirmed 6 positive cases on the registry.
Indian Journal of Medical Research, 2015
Journal of Hematopathology, Sep 14, 2022
International Journal of Laboratory Hematology, Jul 30, 2015
ABSTRACT The term thalassemia intermedia describe a form of thalassemia of intermediate severity,... more ABSTRACT The term thalassemia intermedia describe a form of thalassemia of intermediate severity, between the major transfusion-dependent forms of the disease and the symptomless carrier states. The phenotypic diversity of β-thalassemia results from its underlying genetic diversity. The wide clinical variability of these conditions leads to major difficulties in their management. The molecular basis of thalassemia intermedia is very heterogeneous. The clinical and hematological course of β-thalassemia intermedia is influenced by a number of genetic factors. The main aim of the study was to evaluate the effect of globin and nonglobin genetic modifiers on clinical severity of the disease. The study group consisted of 66 homozygous patients with β-thalassemia [40 transfusion-dependent thalassemia (TDT), 26 nontransfusion-dependent thalassemia (NTDT)]. Hepatosplenomegaly was pronounced in the NTDT group. The presence of associated α-thalassemia was significantly higher in untransfused patients (P < 0.05). The milder β-thalassemia mutations, such as Cap site +1 (A→C), -88 (C→T), and -87 (C→G), were observed mainly in the NTDT group (9.61%) as against patients with TDT (1.25%). The cis-DNA haplotypes, motifs, or polymorphisms around the gamma-globin genes [(AT)x (T)y motif (38.4%), XmnI (76.92%)and the Aγ-δ intergenic region haplotype T (73.07%) and Pre Gγ globin gene haplotype TAG (46.15%)] contributed significantly in amelioration of the disease severity. Our study emphasizes the complexity of genetic interactions that underlie the phenotype of β-thalassemia and highlights the importance of epistatic factors and the regulation of HbF production in β-thalassemia syndromes. © 2015 John Wiley & Sons Ltd.
Annals of Human Genetics, Mar 31, 2017
The Kruppel-like factor 1 (KLF1) gene is an essential transcription factor that is required for t... more The Kruppel-like factor 1 (KLF1) gene is an essential transcription factor that is required for the proper maturation of the erythroid cells. Recent studies have reported that KLF1 variations are associated with increased fetal hemoglobin (HbF) levels. Here we report a novel KLF1 gene variation codon 211 A→G (c.632 A&amp;gt;G) in a family who was referred for hemoglobinopathy screening. Both parents were classical β-thalassemia trait (mother: HbA2 4.1%, HbF 8.6%; father: HbA2 5.5%, HbF 0.6%) codon 15 G→A heterozygous, and the child was β-thalassemia homozygous. Because the mother showed a high HbF level, the genetic determinants for raised HbF were screened. We detected a novel KLF1 gene variant in the mother and the child in the heterozygous state. The co-inheritance of this novel KLF1 variant might have increased the HbF levels in the mother and may have ameliorated the clinical manifestations of the 6-year-old untransfused β-thalassemia homozygous child. Identification of KLF1 gene variants may act as a novel target for increasing HbF levels in patients with β-hemoglobinopathies.
Scandinavian Journal of Rheumatology, Sep 3, 2015
This is a repository copy of Association between the angiotensin-converting enzyme gene insertion... more This is a repository copy of Association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and susceptibility to systemic lupus erythematosus in an Indian population..
Blood Cells Molecules and Diseases, May 1, 2022
INTRODUCTION β-thalassemia is an autosomal recessive disorder of hemoglobin (Hb) production cause... more INTRODUCTION β-thalassemia is an autosomal recessive disorder of hemoglobin (Hb) production caused by a reduced amount (β +) or absence (β 0) of β-globin chain synthesis resulting in a relative excess of unbound α-globin chains that precipitate in erythroid precursors leading to ineffective erythropoiesis. [1] The pathogenesis of β-thalassemia is a complex, multisystem process with different genetic and epigenetic markers influencing the phenotype of the disease. [2] An estimated 1.5% of the global population are carriers of β-thalassemia, with about 60,000 symptomatic individuals born annually. [3] In India, the carrier rate for β-thalassemia varies from 1% to 17% [4,5] among certain high-risk communities with an average frequency of 3-4% [6,7] and an estimated birth of 8000-10,000 babies with severe forms
Annals of Hematology, Apr 20, 2016
An association between maternal age and offspring LTL and the interaction with BD was observed. I... more An association between maternal age and offspring LTL and the interaction with BD was observed. It could be speculated that an influence of oxidative stress during first pregnancy, changes in mitochondrial DNA or even other parent-specific imprinting mechanism, such as DNA methylation, relevant to the neurodevelopment of the brain. To our knowledge, this is the first study evaluating association of maternal age and telomere length in the offspring of families with several members affected by BD. Additional studies are needed to confirm these preliminary findings.
Mutation Research-reviews in Mutation Research, Jul 1, 2021
There is inconsistency in the exact definition of diagnostic levels of HbA2 for β thalassemia tra... more There is inconsistency in the exact definition of diagnostic levels of HbA2 for β thalassemia trait. While many laboratories consider HbA2 ≥4.0 % diagnostic, still others consider HbA2 ≥3.3 % or HbA2 ≥3.5 % as the cut-off for establishing β thalassemia carrier diagnosis. This is because, over the years, studies have described β thalassemia carriers showing HbA2 levels that lie above the normal range of HbA2 but below the typical carrier range of β thalassemia. These, "borderline HbA2 levels", though not detrimental to health, are significant in β thalassemia carrier diagnosis because they can lead to misinterpretation of results. In this review, we have evaluated the prevalence of borderline HbA2 levels and discussed the causes of borderline HbA2 values. We have also compiled an extensive catalogue of β globin gene defects associated with borderline HbA2 levels and have discussed strategies to avoid misdiagnosing borderline HbA2 β thalassemia carriers. Our analysis of studies that have delineated the cause of borderline HbA2 levels in different populations shows that 35.4 % [626/1766] of all individuals with borderline HbA2 levels carry a molecular defect. Among the positive samples, 17 % [299/1766] show β globin gene defects, 7.7 % [137/1766] show α thalassemia defects, 2.7 % [49/1766] show KLF1 gene mutations, 2.3 % [41/1766] show the co-inheritance of β and α thalassemia, 2.0 % [37/1766] show the co-inheritance of β and δ thalassemia and 1.8 % [32/1766] show α globin gene triplication. It appears that a comprehensive molecular work up of the β globin gene is the only definite method to detect borderline HbA2 β thalassemia carriers, especially in populations with a high prevalence of the disease. The presence of associated genetic or acquired determinants may subsequently be assessed to identify the cause of borderline HbA2.
Clinical Genetics
MicroRNAs are the major class of small non-coding RNAs, evolutionary conserved posttranscriptiona... more MicroRNAs are the major class of small non-coding RNAs, evolutionary conserved posttranscriptional regulators of gene expression. Since their discovery in 1993, they have been implicated as master regulators in numerous cellular processes. MicroRNA (miRNA)s regulate gene expression by attenuation and/or mRNA degradation and are commonly associated with cell development, differentiation, and homeostasis. Extensive research in past two decades has provided new insights into the potential implications of miRNA in the onset, progression, and therapeutic nature of miRNAs in disease manifestation. Owing to the novel discoveries, "miRNAs" would probably pave a new direction in therapeutic research. However, "micro" in length miRNAs have attracted considerable attention in numerous other fields. Understanding the functionality of miRNAs, in this review article, we discussed the mechanistic role of miRNAs in human diseases and have outlined most of the recent published work in clinical therapeutics. We have constructed different network models for miRNA and its targets which made us understand their interrelationship and association with diseases. Future research would surely overcome challenges and would introduce new strategies for the utility of miRNAs in a broader setting.
Indian Journal of Pathology and Microbiology
Hemoglobin, 2021
Abstract The β-thalassemias and sickle cell disorders pose a considerable health burden in India.... more Abstract The β-thalassemias and sickle cell disorders pose a considerable health burden in India. Of the more than 10,000 annual births of children with a severe hemoglobinopathy, only around 10.0% are managed optimally. Thus, genetic counseling and prenatal diagnosis (PND) is a valid option for a large and diverse country. Our center was one of the first to initiate PND and we present our experience over 30 years to evaluate the impact of awareness in changing the trends of PND of hemoglobinopathies. Both second and first-trimester diagnoses were undertaken by fetoscopy/cordocentesis and globin biosynthesis/high-performance liquid chromatography (HPLC) analysis of fetal blood and chorionic villus sampling (CVS) and DNA analysis. Over 30 years, 3478 couples (first trimester: 2475; second trimester: 1003) from all over India were offered PND. The number of couples coming in the first trimester increased significantly over each decade and couples coming prospectively increased from 2.5 to 18.4%. A cost-effective stepwise approach was used for molecular analysis. Eight hundred and one fetuses (23.0%) were affected and all except three couples opted for termination of these pregnancies. Genetic counseling and PND is the only way to reduce the burden of disease. With awareness, there was a shift from second trimester to first trimester PND over each decade, with an increasing number of couples coming during the first pregnancy. There are only 15 to 20 centers in India offering PND. We have compared our study with other reports on PND from different regions in India.
Medknow Publications on behalf of Indian Society of Human Genetics, Dec 31, 2005
BACKGROUND : β-Thalassemia (β-thal) is present in practically every caste group in Indians. Molec... more BACKGROUND : β-Thalassemia (β-thal) is present in practically every caste group in Indians. Molecular characterization of β-thal in these groups has revealed an extremely heterogeneous picture. AIM: To identify all the mutations and to detect the novel mutations using a versatile mutation detection technique. MATERIALS AND METHODS: Denaturing gradient gel electrophoresis (DGGE) has been established to scan the entire β-globin gene to localize the mutation followed by DNA sequencing for characterization. The DNA samples from two families referred to us either for prenatal diagnosis or for DNA studies were studied. RESULTS: Atypical DGGE patterns in fragments B & A indicating the presence of the mutation, have been detected in both the families. DNA sequencing revealed two rare patterns fragments with patterns in fragments β-thal mutations [CD 26 (C→T) and-90 (C→T)]. CONCLUSION: DGGE is a useful mutation detection technique to identify β-thal mutations among the heterogeneous Indian population.