Satrupa Das

Primordial dwarfism: overview of clinical and genetic aspects

Primordial dwarfism is a group of genetic disorders which include Seckel Syndrome, Silver–Russell Syndrome, Microcephalic Osteodysplastic Primordial Dwarfism types I/III, II and Meier–Gorlin Syndrome. This genetic disorder group is characterized by intra-uterine growth retardation and post-natal growth abnormalities which occur as a result of disorganized molecular and genomic changes in embryonic stage and, thus, it represents a unique area to study growth and developmental abnormalities. Lot of research has been carried out on different aspects; however, a consolidated review that discusses an overall spectrum of this disorder is not accessible. Recent research in this area points toward important molecular and cellular mechanisms in human body that regulate the complexity of growth process. Studies have emerged that have clearly associated with a number of abnormal chromosomal, genetic and epigenetic alterations that can predispose an embryo to develop PD-associated developmental defects. Finding and associating such fundamental changes to its subtypes will help in re-examination of alleged functions at both cellular and developmental levels and thus reveal the intrinsic mechanism that leads to a balanced growth. Although such findings have unraveled a subtle understanding of growth process, we further require active research in terms of identification of reliable biomarkers for different subtypes as an immediate requirement for clinical utilization. It is hoped that further study will advance the understanding of basic mechanisms regulating growth relevant to human health. Therefore, this review has been written with an aim to present an overview of chromosomal, molecular and epigenetic modifications reported to be associated with different subtypes of this heterogenous disorder. Further, latest findings with respect to clinical and molecular genetics research have been summarized to aid the medical fraternity in their clinical utility, for diagnosing disorders where there are overlapping physical attributes and simultaneously inform about the latest developments in PD biology.

Genetic determinants in ischaemic stroke subtypes: seven year findings and a review.

Stroke is a global health problem and a leading cause of disability worldwide. There have been numerable studies undertaking research on different aspects of ischaemic stroke employing various epidemiological, clinical and molecular parameters. Nevertheless ischaemic stroke being a complex disorder with different subtypes demands equal attention towards its subtypes too. Since there has been enough evidence that disposition to certain subtype is genetically determined and there is a distinct mechanism that influences its development, association studies should focus on subtypes simultaneously while studying specific genes. Data from such studies will thus provide better and intricate findings with regard to heterogenous ischaemic stroke. In the present review we discuss the genes studied by our group over a period of seven years in association with stroke subtypes in a South Indian population and correlate the findings with similar genetic studies from other populations so as to provide an overview of various genes involved in the pathogenesis of ischaemic stroke subtypes.

Association between PDE4D gene and ischemic stroke: recent advancements

Stroke is a severe complication and a leading cause of death worldwide and genetic studies among different ethnicities has provided the basis for involvement of phosphodiesterase 4D (PDE4D) gene in cerebrovascular diseases. Recent advancements have evaluated the role of this gene in stroke and these studies have provided a stronger support for the involvement of this gene in stroke development and few studies also suggest that it may influence outcome. Furthermore, case-control studies and meta-analysis studies have provided strong evidence for certain variants in PDE4D to predispose to stroke only among certain ethnicities. Thus, this review focuses on recent progress made in PDE4D gene research involving genetic, molecular and pharmacological aspect. A strong conclusion has emerged that clearly indicates a pivotal role played by this gene in ischemic stroke globally. Studies have also noticeably highlighted that PDE4D gene/pathway can be a suitable drug target for managing stroke; however, a more comprehensive research is still required to understand the molecular and cellular intricacies this gene plays in stroke development, progression and its outcome.

Association of APOE (E2, E3 and E4) gene variants and lipid levels in ischemic stroke, its subtypes and hemorrhagic stroke in a South Indian population

In the present study we evaluated the association of APOE (E2/E3/E4) polymorphism with ischemic stroke (n=620), its subtypes and hemorrhagic stroke (n=250) in a South Indian population from Telangana. The genotypes were determined using PCR-RFLP while lipid levels were measured using commercially available kits. We found significant difference in the genotypic distribution between hemorrhagic stroke patients and controls for certain genetic models [E2/E2 vs. E2/E4; E3/E3 vs. E2/E3; E3/E3 vs. E2/E4; E4/E4 vs. E2/E3; E4/E4 vs.E2/E4 and E3 vs. E4]. However, no significant difference was observed in genotypic distribution between ischemic stroke patients and controls. On analysing the genotypic distribution between ischemic and hemorrhagic stroke patients, statistically significant difference was observed in specific genetic models [E2/E2 vs. E2/E4; E3/E3 vs. E2/E3; E3/E3 vs. E2/E4; E4/E4 vs. E2/E3 and E4/E4 vs. E2/E4]. In ischemic stroke subtypes analysing for alleles E3 vs. E2 and E3 vs. E4, we found significant association with intracranial large artery (p=0.01), cardioembolic stroke (p=0.001 and p=0.0004) and lacunar stroke (p=0.02). Analysing the association of various genotypes with different lipid levels significant association was observed for VLDL (P=0.000) and for triglyceride (P=0.000) levels with E2/E4 and E3/E4 genotypes in ischemic stroke but not in hemorrhagic stroke. In conclusion, our results suggest that APOE polymorphism does seem to play a role in hemorrhagic stroke and also in the development of specific subtypes of ischemic stroke. Further, in ischemic stroke VLDL and triglycerides levels were found to be significantly associated with E2/E4 and E3/E4 genotypes.

Interleukin 1β (+3954, −511 and −31) polymorphism in chronic periodontitis patients from North India

Abstract Objective. Several studies have implicated the role of interleukin-1 in various chronic diseases including periodontitis. The present study was carried out with an aim to evaluate the role of interleukin 1β polymorphisms, namely +3954C/T, −511C/T and −31T/C, in the development of chronic periodontitis. Materials and methods. Twenty-nine chronic periodontitis patients and 31 healthy controls of North Indian origin from Chhattisgarh were recruited for the study. The genotypes for the three variants were determined using the PCR-RFLP technique and the strength of association between genotypes and periodontitis was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. Results. Analysis for the +3954 allelic and genotypic frequencies of the polymorphism revealed a significant difference in the CT genotype between periodontitits patients and controls (p = 0.03). A significant difference was also observed in the allelic frequencies between the two groups (p = 0.02). For the −511 site, TT genotype revealed a significant association with the disease (p = 0.01). A significant association was also found following the co-dominant model (p = 0.007). However, the −31 polymorphism revealed no significant difference between patients and controls. Conclusions. In conclusion, the present study suggests a strong association of the TT genotype of −511 and CT genotype of +3954 variant of interleukin 1β with chronic periodontitis. However, the −31 variant did not show a significant association with the disease.

E-selectin gene (S128R) polymorphism in hemorrhagic stroke: Comparison with ischemic stroke

Increasing evidence suggests that genetic variation in inflammatory genes plays a pivotal role in pathogenesis of stroke. The aim of the present study was to evaluate the association of E-selectin S128R polymorphism with hemorrhagic stroke and also to evaluate the genotypic and allelic variation with ischemic stroke in a South Indian population from Andhra Pradesh. In this study, we recruited 250 hemorrhagic stroke patients along with 250 age and sex matched controls. The genotypes were determined using PCR-RFLP method and the strength of association between genotypes and hemorrhagic stroke was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. Allelic and genotypic frequencies of the polymorphism differed significantly between hemorrhagic stroke patients and controls (p<0.001). Significant association was also found following dominant (p<0.001) and co-dominant (p<0.001) models. On comparing the genotypic and allelic frequencies between ischemic and hemorrhagic stroke significant difference was found between the two stroke types (p<0.001). In conclusion, we found the AC genotype to be a significant risk factor for hemorrhagic stroke and we also found significant differences in AC genotype and C allele among the two stroke types. The genotypic and allelic variation between the ischemic and hemorrhagic stroke, suggests that E-selectin S128R mediated amplification of leukocytes onto endothelial cells, leading to secondary damage of brain cells is more pronounced in hemorrhagic stroke.

Association of -1382A>G CCL11 gene variant with ischemic stroke, its subtypes and hemorrhagic stroke in a South Indian population

BACKGROUND CCL11 (Eotaxin-1) is an important inflammatory cytokine belonging to the CC family of chemokines associated with a number of infection or inflammation-related diseases such as atherosclerosis and stroke. We investigated the association of CCL11 gene polymorphism rs4795895-1382A>G with ischemic and hemorrhagic stroke. MATERIALS AND METHODS Six hundred and twenty ischemic stroke patients, 620 age- and sex-matched healthy controls, and 220 hemorrhagic stroke patients, 220 age- and sex-matched healthy controls were included in the present study. The CCL11 gene polymorphism rs4795895-1382A>G was determined using PCR-RFLP technique. RESULTS We found a statistically significant difference in the genotypic distribution between ischemic stroke patients and controls (For GG vs. AA, χ² = 7.604; P < 0.001, Odds ratio = 2.793; 95% CI = 1.308-5.9). For GG vs. AA + AG, χ² = 44.8, P < 0.001, Odds ratio = 2.382 (95% CI = 1.842-3.081). A significant difference was observed in the frequency of G and A alleles in patients and controls (For G vs. A, χ² = 43.26; P < 0.001, Odds ratio = 2.127; 95% CI = 1.693-2.672). Statistically significant difference was observed in the genotypic distribution between hemorrhagic stroke patients and controls (For GG vs. AG, χ² = 26.78; P = 0.001, Odds ratio = 3.5; 95% CI = 2.162-5.824). A significant difference was observed in the frequency of G and A alleles in patients and controls (For G vs. A, χ² = 41.98; P = 0.001, Odds ratio = 4.1; 95% CI = 2.61-6.44). CONCLUSION The results of the present study show that the GG genotype is a significant risk factor for ischemic as well as hemorrhagic stroke. Further, the frequency of the GG genotype was observed to be higher in hemorrhagic stroke patients in comparison with ischemic stroke. Evaluating the association with ischemic stroke subtypes, a significant association was observed with intracranial large artery atherosclerosis and lacunar stroke.

Research advances in Apert syndrome

Apert syndrome is one of the several genetic syndromes associated with craniosynostosis, a condition that includes premature fusion of one or multiple cranial sutures. There has been significant clinical variation among different sutural synostoses and also within particular suture synostosis. Enormous progress has been made in identifying various mutations associated with Apert Syndrome. Although a causal gene has been defined, the precise role of this mutation in producing craniofacial dysmorphology and other related abnormalities is in the process of discovery. Most of the understanding regarding this rare disorder has been possible due to mouse models that have helped in deciphering the elements of this rare human disease. Thus, molecular and cellular understanding of the disease has taken a leap and further with the advent of technology definitive diagnosis of the syndrome is no more of an issue. In this review, we have discussed and consolidated the possible molecular studies that have contributed in understanding of this rare syndrome. This article may help clinicians and researchers to inform about the latest progress in Apert syndrome.

MTHFR Gene (C677t) Polymorphism in Ischemic Stroke, its Subtypes and Hemorrhagic Stroke in a South Indian Population.

Objective: We investigated the association of MTHFR C677T polymorphism with ischemic stroke, its subtypes and hemorrhagic stroke in a South Indian Population from Andhra Pradesh. Methods: Six hundred and twenty ischemic stroke patients, 220 hemorrhagic stroke patients and 620 age and sex matched healthy controls, were included in the present study. The polymorphism was determined using PCR-RFLP technique. Results: The strength of association between genotypes and stroke types was measured by the odds ratio with 95% confidence interval and chi-squared analysis. We found significant association of the CT genotype with ischemic stroke as well as haemorrhagic stroke (p<0.05). Further, evaluating the association of this polymorphism with stroke subtypes, we found significant association with intracranial large artery (p<0.05), lacunar stroke (p<0.05) and undetermined etiology (p<0.05). However, there was no significant difference in genotypic or allelic frequencies between ischemic and hemorrhagic strokes. Conclusion: Our study suggests that MTHFR (C677T) is an important risk factor for ischemic stroke, its subtypes and hemorrhagic stroke in the South Indians from Andhra Pradesh but it cannot help in distinguishing between the two types of stroke.

Genetic Understanding of Stroke Treatment: Potential Role for Phosphodiesterase Inhibitors

Phosphodiesterase (PDE) gene family is a large family having at least 21 genes and multiple versions (isoforms) of the phosphodiesterase enzymes. These enzymes catalyze the inactivation of intracellular mediators of signal transduction such as cAMP and cGMP and therefore, play a pivotal role in various cellular functions. PDE inhibitors (PDEI) are drugs that block one or more of the five subtypes of the PDE family and thereby prevent inactivation of the intracellular cAMP and cGMP by the respective PDE-subtypes. The first clinical use of PDEI was reported almost three decades ago. Studies later found the ability of these compounds to increase the levels of ubiquitous secondary messenger molecules that can cause changes in vascular tone, cardiac function and other cellular events and thus these findings paved the way for their use in various medical emergencies. PDEs are found to be distributed in many tissues including brain. Therefore, new therapeutic agents in the form of PDEI are being explored in neurodegenerative diseases including stroke. Although studies have revealed their use in cerebral infarction prevention, their full-fledged application in times of neurological emergency or stroke in specific has been very limited so far. Nevertheless, recent investigations suggest PDE4 and PDE5 inhibitors to play a vital role in mitigating stroke symptoms by modulating signaling mechanisms in PDE pathway. Further, extensive research in terms of their pharmacological properties like dosing, drug specific activities, use of simultaneous medications, ancillary properties of these compounds and studies on adverse drug reactions needs to be carried out to set them as standard drugs of use in stroke.