Biswanath Sarkar

Environmental and Familial Risk Factors of Parkinsons Disease: Case-Control Study

BACKGROUND While the cause of Parkinsons disease (PD) remains unknown, evidence suggests certain environmental factors, such as well water drinking, herbicides, pesticides exposure and neurotoxins, may trigger the chain of oxidative reactions culminating in the death of dopaminergic neurons in substantia nigra to cause Parkinsonism. To investigate the possible impact of environmental risk factors for idiopathic PD, a case-control study was performed in the Eastern India. METHODS During the period from January 1st, 2006 and December 10th, 2009, 175 PD patients (140 men, 35 women) and 350 non-Parkinson age-sex matched controls were included in the study. Subjects were given a structured neurological examination and completed an administered questionnaire which elicited detailed information on demographic data, pesticides, herbicides family history, occupation, dietary and smoking habits. RESULTS The multivariate analysis revealed that family history of PD, pesticide exposure, exposure to toxins other than pesticides and herbicides, rural living and previous history of depression were associated with increased risk of PD, whereas, smoking appeared to be a protective factor. Well water drinking for at least five years, though a significant risk factor on univariate analysis (OR = 4.5, 95% CI = 2.1-9.9), could not be proved significant in multivariate analysis. Head trauma, vegetarian dietary habit, occupation involving physical exertion and exposure to domestic pets were not as significant risk factors. CONCLUSION Results of our study support the hypothesis of multifactorial etiology of PD with environmental factors acting on a genetically susceptible host.

Menopause versus aging: The predictor of obesity and metabolic aberrations among menopausal women of Karnataka, South India.

Context: Increased incidences of cardiovascular disorder and metabolic syndrome particularly after menopause have raised curiosity for the underlying factors. However, it is still a debate whether age or menopausal transition is a greater contributor. Aims: To elucidate the inter-relationships of age, menopause, and associated obesity and to assess their independent effects on aggravation of cardio metabolic risk factors in postmenopausal women. Settings and Design: Four hundred two women aged between 30 and 75 years were recruited in a cross-sectional study from Southern India. Three hundred sixteen participants exempting exclusion criteria, comprising of 169 premenopausal and 147 postmenopausal women were finally included. Materials and Methods: Anthropometric measurements such as weight, height, waist circumference (WC), hip circumference (HC), fat percentage, basal metabolic rate (BMR), and blood pressure were taken. Fasting plasma glucose, postprandial glucose, glycated hemoglobin (HbA1c), lipid profile, and C-reactive protein (CRP) were also measured. Statistical Analysis Used: Independent t-test, Analysis of covariates (ANCOVA), Pearsons correlation coefficients and multiple stepwise linear regression model analysis were done. Results: A significant increase in physical and metabolic factors was observed in postmenopausal women compared to premenopausal women except WC and HbA1c. Contrastingly, high-density lipoprotein cholesterol (HDL) levels and BMR were significantly decreased. After adjusting for BMI and age, the significant differences in the variables through the menopausal transition persisted, including an increase in WC. Significant correlation was observed between age and measures of general obesity such as BMI (P < 0.05) and fat percentage (P < 0.001) but not with central obesity indices. Menopausal status and WC exerted an independent effect on most of the metabolic risk factors (P < 0.001 or P < 0.01). Fat percentage was the predicting variable for CRP, HbA1c, diastolic blood pressure (P < 0.001), and HDL (P < 0.01). But Age showed independent effect only on HbA1c. Conclusions: Menopausal transition brings about anomalies in total body composition characterized by an increased body fat mass and central adiposity. This creates a compatible atmosphere for abnormal metabolism and aggravated cardio metabolic risk factors. Thus, menopausal status and associated obesity is the major predictor of metabolic aberrations over age in menopausal women.

Molecular Relatedness of The Aboriginal Groups of Andaman and Nicobar Islands with Similar Ethnic Populations

Abstract The aboriginal tribal groups living in the Andaman and Nicobar Islands are thought to be the descendants of people who were part of the early human dispersal into the Southeast Asia. However, the origin of the tribes of Andaman, the region from where the aboriginals arrived and the route of their migration are still a matter of great speculation. To explore the origin and affinities of the Andaman Islanders, we studied the polymorphism at fifteen autosomal short tandem repeat (STR) loci, mitochondrial control region sequences and eight Y chromosomal STR loci in 194 blood samples, of which 94 samples were from the Andaman Negritos (24 Great Andamanese and 70 Jarawas) and 100 Nicobarese, a Mongoloid group of Nicobar Island and evaluated their relatedness with similar ethnic groups of India, Southeast Asia and Africa. Our results clearly demonstrate that the aboriginal populations of the Andaman Islands – the Great Andamanese and the Jarawas constitute an independent cluster, separating out from all other populations selected in the study. The Nicobarese show a close affinity with the Mongoloid population of Southeast Asia. The distinct genetic identity of the aboriginal populations of the Andaman Islands and other Asian and African populations deciphered by nuclear and mitochondrial DNA diversity suggest that (i) either the aboriginals of Andaman are one of the surviving descendents of settlers from an early migration out of Africa who remained in isolation in their habitat in Andaman Islands, or (ii) they are the descendents of one of the founder populations of modern humans.

The promise of discovering population-specific disease-associated genes in South Asia

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population, but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identify 81 unique groups, of which 14 have estimated census sizes of more than a million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identify multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an under-appreciated opportunity for reducing disease burden among South Asians through the discovery of and testing for recessive disease genes.The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identified multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an underappreciated opportunity for decreasing disease burden among South Asians through discovery of and testing for recessive disease-associated genes.

Approaches in type 1 diabetes research: A status report

Type 1 diabetes is a multifactorial disease with an early age of onset, in which the insulin producing β cell of the pancreas are destroyed because of autoimmunity. It is the second most common chronic disease in children and account for 5% to 10% of all diagnosed cases of diabetes. India is having an incidence of 10.6 cases/year/100,000, and recent studies indicate that the prevalence of type 1 diabetes in India is increasing. However in view of poor health care network, there is no monitoring system in the country. Of the 18 genomic intervals implicated for the risk to develop type 1 diabetes, the major histocompatibility complex (MHC) region on chromosome 6p21.31 has been the major contributor estimated to account for 40-50%, followed by 10% frequency of INS-VNTR at 5’ flanking region of the insulin gene on chromosome 11p15.5. However, population studies suggest that > 95% of type 1 diabetes have HLA-DR3 or DR4, or both, and in family studies, sibling pairs affected with type 1 diabetes have a non-random distribution of shared HLA haplotypes. As predisposing genetic factors such as HLA alleles are known, immunological interventions to prevent type 1 diabetes are of great interest. In the present study we have reviewed the status of molecular genetics of the disease and the approaches that need to be adopted in terms of developing patient and suitable control cohorts in the country.

Peripheral markers for oxidative stress in Parkinson’s disease patients of Eastern India

Oxidative stress is thought to play a major role in the pathogenesis of Parkinson’s disease (PD). Neurons are highly susceptible to a defective antioxidant scavenging system, thus inducing oxidative changes in human red blood cells (RBCs), in vivo and in vitro. Previous studies on oxidative stress in RBCs in patients with PD have yielded controversial results claiming unaltered activity to reduced activity. We have thus undertaken this study to investigate the possibility of oxidative damage to the RBCs in PD by measuring the cytosolic antioxidant enzymes viz., catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (G-Px). The biochemical parameters were measured in erythrocytes of 80 PD patients and 80 normal age-matched healthy controls. The enzymes activities were correlated with age of patients, age of onset of disease, duration of disease, United Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr stage. Patients with PD had higher red blood corpuscle (RBC) activity of SOD. The CAT, and G-Px activities were significantly lower in patients with PD compared to the controls. Erythrocyte SOD, CAT and G-Px were markedly lower in those PD patients who were suffering for a greater duration of the disease and in advanced cases of PD. A significant (P < 0.05) negative correlation of enzyme activities with disease duration, UPDRS score and Hoehn and Yahr stage of the disease was found. Results of our present study concludes the implication of oxidative stress as one of the risk factors, which can initiate or promote neurodegeneration in PD by playing a role in dopaminergic neuronal loss and was correlated to the severity of the disease.

Absence of Commonly Reported Leucine-Rich Repeat Kinase 2 Mutations in Eastern Indian Parkinson's Disease Patients

BACKGROUND Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2; PARK8) encoding dardarin, implicated in patients with autosomal dominant and sporadic Parkinsons disease (PD) among different ethnic groups (Ashkenazi Jews, North African Arabs, Basques) might be of some help in diagnostic screening and genetic counseling. AIM OF THE STUDY We investigated the seven common mutations spanning exons 31, 35, and 41 reported in the LRRK2 gene among Eastern Indian patients with PD. METHODS Mutations R1441G, R1441C, R1441H, G2019S, Y1699C, I2020T, and I2012T were screened in 320 individuals (PD, 150 and controls, 170) by direct sequencing. RESULTS We did not observe any of these abovementioned mutations in our studied individuals. CONCLUSION We conclude that these mutations are rare causes of PD in the Eastern Indian population and, therefore, of little help for genetic counseling and diagnostic purposes.

Polymorphic haplotypes of CRELD1 differentially predispose Down syndrome and euploids individuals to atrioventricular septal defect

To explore the role of CRELD1 variants on congenital heart defects, we sequenced the entire reading frame of CRELD1 in the samples from Kolkata and adjoining areas. Nearly, 400 participants were included in the genetic association study and they were stratified as Down syndrome (DS) with atrioventricular septal defect (AVSD), DS without AVSD, euploid with AVSD, and euploid without AVSD. A significant association was found between AVSD and three polymorphisms, namely rs9878047 (c.1049‐129T > C), rs3774207 (c.1119C > T), and rs73118372 (c.1136T > C) among the Down syndrome and euploid individuals. The polymorphism rs73118372, involves a transition (c.1136T > C) that leads to change in amino acid methionine to threonine which alters protein secondary structure as confirmed by the bioinformatics software SOPMA. In addition, two haplotypes, C‐T‐C and C‐T‐T, in the order of loci rs9878047‐rs3774207‐rs73118372 were associated with incidence of AVSD among euploid and Down syndrome, with a slightly higher odds ratio in the later group. We hypothesize that these haplotypes increase the risk of AVSD, and the susceptibility is exacerbated in DS, possibly due to the trisomy 21 genetic background. Moreover, we report for the first time on an interaction between the mutant alleles of rs3774207 and rs73118372 which could disrupt the delicate balance between different CRELD1 isoforms.

A novel polymorphism in codon 25 of the KRAS gene associated with gallbladder carcinoma patients of the eastern part of India.

Gallbladder cancer (GBC) is more prevalent than other cancers in North India. The asymptomatic nature of the disease is a problem in the diagnosis and treatment. Analysis of oncogenes or tumor suppressor genes could be of importance in this regard. KRAS is the most frequently mutated member and is said to be one of the most activated oncogenes. The present study was aimed to determine the role of intragenic variants in the KRAS gene, in the progression of GBC in the eastern part of India. Sixty gallbladder carcinoma subjects (13 men and 47 women) with histologically proven diagnosis and 90 individuals (14 men and 76 women) who have no diagnosed cancer were included in the present study. All single-nucleotide polymorphisms present in exons 1 and 2 were analyzed by polymerase chain reaction followed by sequencing. We could not find the most frequently reported mutations at codons 12, 13, and 61 of the KRAS gene that occur in human malignancies. However, in this study, we detected one novel polymorphism at codon 25 (CAG>CAT; Gln25His) in exon 1 of the KRAS gene in both germline and tissue DNA. Multivariable logistic regression analysis with adjustment for age and sex revealed that the Gln25His variant of the KRAS gene was significantly associated with GBC. In silico analysis has validated the KRAS p.Q25H polymorphism as a disease-causing variant. Further, screening of the DNA samples in a cohort of ancestral tribal populations from various parts of the country without information on the phenotype, however, revealed the presence of the previously reported codon 12 and 25 polymorphisms, thereby indicating that the novel variant is population specific in the region.

Evaluating intra-genetic variants of DJ-1 among Parkinson's disease patients of Eastern India

Abstract Objectives: Mutations in the DJ-1 gene have been described in autosomal recessive Parkinsons disease (PD) of European ancestry, Ashkenazi Jews, and Afro-Caribbean patients. Up to date, there is a lack of information about the prevalence of DJ-1 mutations among Indian PD patients. Materials and methods: In this study, we examined for DJ-1 mutations in Eastern Indian PD patients. Exons (no. 2-7) and intron boundaries of the DJ-1 gene were screened in 300 individuals (PD, 150; controls, 150) by direct sequencing. Results: A total of six intronic variants (IVS4+30T>G, IVS4+45G>A, IVS4+46G>A, IVS4-98G>A, IVS5+31G>A and IVS5+69G>C) were detected including one novel intronic change (IVS5+69G>C). Clinical features of the two patients exhibiting IVS5+69G>C (novel change) were compared and both were found to have early onset PD. IVS4+30T>G, IVS4+45G>A, and IVS4+46G>A were found to be present equally both in the patient and control cohorts. We did not find any DJ-1 mutations in our study. Conclusion: Our results suggest that, unlike Parkin, pathogenic DJ-1 mutations seem to be restricted in certain populations and are unlikely to be of clinical importance in the eastern part of India.