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Aim was to analyze predictors of burden among primary caregivers (CGs) of Indian Parkinson's disease (PD) patients. 150 PD patients were administered using Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr Scale (H&Y), Montgomery Asberg Depression Rating Score (MADRS) and Mini Mental State Examination (MMSE) in this cross-sectional evaluation study. CG burden was assessed by Caregiver's Burden Scale (CBS), Hospital Anxiety and Depression Scale (HADS), SF-36 and 20-item Burden Assessment Schedule (BAS). Linear regression methods were used to evaluate factors contributing to burden and stress. Mean age of CG was 50.38±16.04 (range: 25-83 yrs). Marital status of CGs was noted to have significant relationship with CBS score (F=9.525, P<0.0001). Siblings (brother/sister) reported the highest CBS score while the wives reported the least. Correlations were strong between CBS and HADS anxiety (r=0.228, P=0.0048) and HADS depression (r=0.2172, P=0.0076). High correlations were found in caregiving duration, patients' stage of illness and motor disability among all the scales (CBS, HADS, SF36) determined. Step-wise regression analysis showed UPDRS (beta=1.364-0.202 ranging among all scales) and H&Y stages (beta=2.786-7.257) to have the strongest influence on CGs. CGs of patients with depression (MADRS: P=0.007 (SF36 mental) and dementia (MMSE: P=0.01) experienced greater stress. Social and financial status was disrupted in ~60% to 80% of the CGs. Motor imbalances with disability of PD patients and severity of disease are the main factors contributing to burden and stress in CGs., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Alcohol dependence is a chronic, progressive neurobiological brain disorder. Previous research reported an inverse association between ethanol drinking and cerebral neuropeptide Y (NPY) levels. There are conflicting results of studies on NPY gene polymorphisms in association with alcohol dependence in humans., Methods: To assess the role of the NPY gene in alcohol dependence, we genotyped three polymorphisms--in a sample of 195 subjects from the Kota population (80 alcohol dependence and 115 controls) and 141 subjects from the Badaga population (80 alcohol dependence and 61 controls). Phenotype was defined based on the DSM-IV criteria. Genotyping was performed using sequencing. Association of the NPY gene with alcohol dependence was tested by using logistic regression and haplotype analyses and linkage disequilibrium., Results: All three polymorphisms were found to be in the Hardy-Weinberg equilibrium in both populations. The results of our study reveal a significant association between G1258A and alcohol dependence in both the Kota and Badaga populations. The linkage disequilibrium between the markers is not strong or significant. Haplotype analysis also did not show significant association between the NPY gene and alcohol dependence., Conclusion: These data support the hypothesis that alcohol dependence is influenced by the NPY G1258A polymorphism in Indian populations., (Copyright © 2013 S. Karger AG, Basel.)

Background: The microsomal epoxide hydrolase is a phase II enzyme of the biotransformation. The human epoxide hydrolase 1 (EPHX1) gene lies in the chromosomal region 1q42.1 and exhibits polymorphism. Two single nucleotide polymorphisms (SNPs) have been described in the coding region of the EPHX1 gene that produces two protein variants., Subjects and Methods: A total of 604 samples belonging to 13 Indian populations were included in this study. Based on the DSM-IV criteria, 184 individuals from Kota population were classified into alcoholism cases (100) and controls (84). Genotypes of Tyr113His and His139Arg polymorphisms in the EPHX1 gene were determined using PCR and sequencing. Associations were tested using Pearson's χ(2) test and haplotype analyses., Results: We found significant association between EPHX1 gene Tyr113His polymorphism and alcoholism in the Kota population (T vs. C: OR = .615, 95% CI = .399-.949, p = .027; TT vs. CC + CT: OR = .536, 95% CI = .297-.969, p = .038). The very slow activity haplotype CA (113His-139His) was also found to be associated with alcohol dependence (p = .048). Analysis of additional populations demonstrated that the Tyr113His polymorphism significantly deviated from Hardy-Weinberg equilibrium in four populations but only one population deviated for the His139Arg locus. All populations shared the four possible two-site haplotypes. Linkage disequilibrium between these two loci was not significant in any of the population studied., Conclusion: EPHX1 gene polymorphisms and haplotypes are associated with an increased risk for alcoholism in the Kota population. This is the first report from India that will serve as a template for future investigations of the prevalence of EPHX1 alleles in association with various clinical entities.

It is well established that the central dopaminergic reward pathway is likely involved in alcohol intake and the progression of alcohol dependence. Dopamine transporter (DAT1) mediates the active re-uptake of DA from the synapse and is a principal regulator of dopaminergic neurotransmission. The gene for the human DAT1 displays several polymorphisms, including a 40-bp variable number of tandem repeats (VNTR) ranging from 3 to 16 copies in the 3'-untranslated region (UTR) of the gene. To assess the role of this gene in alcoholism, we genotyped the VNTR of DAT1 gene in a sample of 206 subjects from the Kota population (111 alcohol dependence cases and 95 controls) and 142 subjects from Badaga population (81 alcohol dependence cases and 61 controls). Both populations inhabit a similar environmental zone, but have different ethnic histories. Phenotype was defined based on the DSM-IV criteria. Genotyping was performed using PCR and electrophoresis. The association of DAT1 with alcoholism was tested by using the Clump v1.9 program which uses the Monte Carlo method. In both Kota and Badaga populations, the allele A10 was the most frequent allele followed by allele A9. The genotypic distribution is in Hardy-Weinberg equilibrium in both cases and control groups of Kota and Badaga populations. The DAT1 VNTR was significantly associated with alcoholism in Badaga population but not in Kota population. Our results suggest that the A9 allele of the DAT gene is involved in vulnerability to alcoholism, but that these associations are population specific., (Copyright © American Academy of Addiction Psychiatry.)

Unlabelled: The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Acetylation catalysed by the NAT2 is an important process in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. Polymorphism in N-acetyltransferase 2 gene was reported to be associated with the susceptibility of various cancers., Objective: The aim of our study was to determine whether there is any association between the susceptibility to oral cancer amongst the variations of NAT2 genotypes., Design: This study was carried out in 157 patients with oral cancer. The control group consisted of 132 healthy volunteers. The most common polymorphisms rs1799929, rs1799930 and rs1799931 on the NAT2 gene were screened for the genotypes using TaqMan allelic discrimination., Results: All the three SNPs were polymorphic with minor allele frequency of 0.339, 0.372 and 0.061 for rs1799929, rs1799930 and rs1799931, respectively. None of the polymorphic site deviated from HWE in controls. There were no significant differences in genotype or allele frequencies of three SNPs between controls and cases with oral cancer. Risk of oral cancer development for the carriers of the individual deduced phenotypes was also not statistically significant. Of the 3 studied polymorphisms, 2 were in strong LD and form one haplotype block. None of the haplotype had shown significant association with the oral cancer., Conclusions: Our study concludes that the NAT2 genotypes, phenotypes and haplotypes are not involved in the susceptibility to oral cancer in South Indian subjects., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The Siddis (Afro-Indians) are a tribal population whose members live in coastal Karnataka, Gujarat, and in some parts of Andhra Pradesh. Historical records indicate that the Portuguese brought the Siddis to India from Africa about 300-500 years ago; however, there is little information about their more precise ancestral origins. Here, we perform a genome-wide survey to understand the population history of the Siddis. Using hundreds of thousands of autosomal markers, we show that they have inherited ancestry from Africans, Indians, and possibly Europeans (Portuguese). Additionally, analyses of the uniparental (Y-chromosomal and mitochondrial DNA) markers indicate that the Siddis trace their ancestry to Bantu speakers from sub-Saharan Africa. We estimate that the admixture between the African ancestors of the Siddis and neighboring South Asian groups probably occurred in the past eight generations (∼200 years ago), consistent with historical records., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Cytochrome P450 (CYP) is a super family of mixed-function oxidases that are responsible for the human metabolism of drugs and endogenous compounds, as well as environmental and dietary substances. Many CYP enzymes function in the liver, but presence of CYP2E1 in the brain is demonstrating its role in both nicotine and ethanol metabolism. To examine the association between CYP2E1 polymorphism and the risk of oral cancer, we performed a case-control study on a south Indian population. 157 patients with oral cancer and 132 age and sexmatched controls were recruited. Three SNPs of the CYP2E1 gene [4768G>A (p. V179I, dbSNP rs6413419), CYP2E1-1295G>C (dbSNP rs3813867) and CYP2E1&#95;-1055C>T (dbSNP rs2031920)] were genotyped using TaqMan allelic discrimination. The V179I locus is monomorphic in the study subjects, whereas rs3813867 and rs2031920 are co-inherited with a minor allele frequency of 0.022. None of the polymorphic sites deviated from HWE in controls. A much lesser frequency of the uncommon c2 allele was seen in our control subjects than in Caucasians and East Asians. There were no significant differences between oral cancer and controls in the distribution of either allelic or genotype frequencies. None of the haplotypes showed a significant association with oral cancer. Our results suggest that CYP2E1 is not a major or independent determinant in the pathogenesis of oral cancer in south Indians.

Several independent lines of evidence for genetic contributions to vulnerability to alcoholism exist. Dopamine is thought to play a major role in the mechanism of reward and reinforcement in response to alcohol. D2 dopamine receptor (DRD2) gene has been among the stronger candidate genes implicated in alcoholism. In this study, alcohol use was assessed in 196 randomly selected Kota individuals of Nilgiri Hills, South India. Six DRD2 SNPs were assessed in 81 individuals with alcoholism and 151 controls to evaluate the association between single nucleotide polymorphisms (SNPs) and alcoholism. Of the three models (dominant, recessive, and additive) tested for association between alcoholism and DRD2 SNPs, only the additive model shows association for three loci (rs1116313, TaqID, and rs2734835). Of six studied polymorphisms, five are in strong linkage disequilibrium forming onesingle haplotype block. Though the global haplotype analysis with these five SNPs was not significant, haplotype analysis using all six SNPs yielded a global P value of .033, even after adjusting for age. These findings support the importance of dopamine receptor gene polymorphisms in alcoholism. Further studies to replicate these findings in different populations are needed to confirm these results.

Hypertension is an independent determinant of cardiovascular risk, a phenotype that usually has a strong genetic component. Neuropeptide Y (NPY) plays an important role in BP homeostasis. The aim of this study was to investigate the possible influence of NPY polymorphisms on hypertension in a South Indian population. A total of 252 subjects (132 controls and 120 hypertensives) were analysed for T1128C, G1258A and A7735G polymorphisms in the NPY gene. Body mass index (BMI), pulse, SBP and DBP were assessed. Direct sequencing of PCR products was adopted for genotyping. All three polymorphisms were found to be in Hardy-Weinberg equilibrium. Additive, dominant and recessive models were tested using multivariate regression analysis. The results of our study reveal a significant association between T1128C and hypertension even after adjusting for age, sex and BMI. The adjusted OR (95% confidence interval) for the recessive model was 0.56 (0.33-0.95). The other two polymorphic sites (G1258A and A7735G) are not associated with hypertension. The Pro7 allele of the T1128C polymorphic site-containing haplotype (CGA) is associated with hypertension (P=0.049), but the combined haplotypes did not show any evidence of haplotype-phenotype association (global P=0.129). These data support the hypothesis that hypertension is influenced by the NPY T1128C polymorphism.

Background/objectives: Neuropeptide Y (NPY) gene has been shown to have a critical role in the regulation of satiety, reproduction, central endocrine and cardiovascular systems. Among the primary functions associated with NPY are its acute effects on feeding behavior and energy expenditure. The aim of this study is to evaluate the relationship between obesity and NPY gene polymorphisms in a South Indian Population., Subjects/methods: Three polymorphisms in NPY gene (Leu7Pro, Ser50Ser and A7735G) were analyzed in 263 individuals of an endogamous Kota population. On the basis of body mass index (BMI), they were divided into two groups. Associations were tested using logistic regression and haplotype analyses and linkage disequilibrium (LD)., Results: There was no evidence of deviation from Hardy-Weinberg equilibrium. Logistic regression analysis did not reveal significant association with obesity and NPY single-nucleotide polymorphisms (SNPs) in the present study. All three SNPs were in weak LD with low r (2) values. Haplotype analysis also did not yield significant association between NPY gene and obesity (global P=0.756)., Conclusions: Our study did not validate the association between previously implicated SNPs in NPY gene and obesity in an Indian population. Population-specific validation of putative associations has far reaching implications for the future personal genomics medicine applications.

The dopamine transporter (DAT1) is a membrane spanning protein that binds the neurotransmitter dopamine and performs re-uptake of dopamine from the synapse into a neuron. The gene encoding DAT1 consists of 15 exons spanning 60 kb on chromosome 5p15.32. Several studies have investigated the possible associations between variants in DAT1 gene and psychiatric disorders. The present study aimed to determine the distribution of the variable number of tandem repeat (VNTR) polymorphism in the 3' untranslated region of DAT1 in 12 Indian populations. A total of 471 healthy unrelated individuals in 12 Indian populations from 3 linguistic groups were included in the present study. The analysis was carried out using PCR and electrophoresis. Overall, 4 alleles of the DAT1 40-bp VNTR, ranging from 7 to 11 repeats were detected. Heterozygosity indices were low and varied from 0.114 to 0.406. The results demonstrate the variability of the DAT1 40-bp VNTR polymorphism in Indian populations and revealed a high similarity with East Asian populations.

The human dopaminergic system is a significant focal point of study in the fields of neuropsychiatry and pharmacology, plus it is also a promising nuclear DNA marker in studies of human genome diversity. In this study, we assayed six polymorphic markers in the dopamine D2 receptor gene (DRD2) in 482 unrelated individuals from nine ethnic populations of India. Our results demonstrate that the six markers are highly polymorphic in all populations and the constructed haplotypes show a high level of heterozygosity. Out of the eight possible three-site haplotypes, all populations commonly shared only three haplotypes. The haplotypes exhibited fairly high frequencies across multiple populations; Kurumba population showed all eight three-site haplotypes. The ancestral haplotype (B2-D2-Al) was observed at high frequency only in the Siddi population. Haplotypes based on all six markers revealed 16 haplotypes, out of which only 6 are most common with a frequency of greater than 5% in at least one of the nine populations. But only three haplotypes were shared by all nine populations with the cumulative frequency ranging from 80.8% (Kurumba) to 96.6% (Onge). Great variation in levels of linkage disequilibrium (LD) was detected, ranging from complete LD in the Badaga to virtually no LD in the Siddi. This range of LD likely reflects different population histories, such as African ancestry in the Siddi and recent founding events in the population isolates, Badaga and Kota.

We have analyzed 7,137 samples from 125 different caste, tribal and religious groups of India and 99 samples from three populations of Nepal for the length variation in the COII/tRNA(Lys) region of mtDNA. Samples showing length variation were subjected to detailed phylogenetic analysis based on HVS-I and informative coding region sequence variation. The overall frequencies of the 9-bp deletion and insertion variants in South Asia were 1.9 and 0.6%, respectively. We have also defined a novel deep-rooting haplogroup M43 and identified the rare haplogroup H14 in Indian populations carrying the 9-bp deletion by complete mtDNA sequencing. Moreover, we redefined haplogroup M6 and dissected it into two well-defined subclades. The presence of haplogroups F1 and B5a in Uttar Pradesh suggests minor maternal contribution from Southeast Asia to Northern India. The occurrence of haplogroup F1 in the Nepalese sample implies that Nepal might have served as a bridge for the flow of eastern lineages to India. The presence of R6 in the Nepalese, on the other hand, suggests that the gene flow between India and Nepal has been reciprocal., (Copyright (c) 2008 S. Karger AG, Basel.)

Seven ADH genes, identified until now, located in the long arm of human chromosome 4, produce seven different isozymes involved in the metabolism of ethanol to acetaldehyde. Of the more than 500 SNPs reported in the coding and non-coding regions of these genes in the world databases, 11 are more extensively studied. Three SNPs, ADH1B Arg47His (Exon3), ADH1B Arg369Cys (Exon9) and ADH1C Val349Ile (Exon8), are functionally validated in terms of phenotype-genotype correlations and are in specific linkage disequilibrium (LD) with non-coding SNPs. However, the frequency of each SNP and configuration of LD varies among populations. The Indian populations studied were conspicuous by the complete absence of African specific allele ADH1B*369Cys, the negligible frequency of East Asian specific ADH1B*47His allele and the presence of a novel SNP ADH1B A3529G (Intron3). The ADH1C*349Ile was the only functional allele polymorphic with a strong LD block in all the populations studied and the high F(st) value observed for the non-coding ADH1B Rsa1 variant was in conformity with world populations., (Copyright 2007 Wiley-Liss, Inc.)

Background: India is a country with enormous social and cultural diversity due to its positioning on the crossroads of many historic and pre-historic human migrations. The hierarchical caste system in the Hindu society dominates the social structure of the Indian populations. The origin of the caste system in India is a matter of debate with many linguists and anthropologists suggesting that it began with the arrival of Indo-European speakers from Central Asia about 3500 years ago. Previous genetic studies based on Indian populations failed to achieve a consensus in this regard. We analysed the Y-chromosome and mitochondrial DNA of three tribal populations of southern India, compared the results with available data from the Indian subcontinent and tried to reconstruct the evolutionary history of Indian caste and tribal populations., Results: No significant difference was observed in the mitochondrial DNA between Indian tribal and caste populations, except for the presence of a higher frequency of west Eurasian-specific haplogroups in the higher castes, mostly in the north western part of India. On the other hand, the study of the Indian Y lineages revealed distinct distribution patterns among caste and tribal populations. The paternal lineages of Indian lower castes showed significantly closer affinity to the tribal populations than to the upper castes. The frequencies of deep-rooted Y haplogroups such as M89, M52, and M95 were higher in the lower castes and tribes, compared to the upper castes., Conclusion: The present study suggests that the vast majority (> 98%) of the Indian maternal gene pool, consisting of Indio-European and Dravidian speakers, is genetically more or less uniform. Invasions after the late Pleistocene settlement might have been mostly male-mediated. However, Y-SNP data provides compelling genetic evidence for a tribal origin of the lower caste populations in the subcontinent. Lower caste groups might have originated with the hierarchical divisions that arose within the tribal groups with the spread of Neolithic agriculturalists, much earlier than the arrival of Aryan speakers. The Indo-Europeans established themselves as upper castes among this already developed caste-like class structure within the tribes.