V.R. Rao

A validation study of type 2 diabetes-related variants of the TCF7L2, HHEX, KCNJ11, and ADIPOQ genes in one endogamous ethnic group of North India.

The aim of this study was to validate the single nucleotide polymorphisms (SNPs) of four candidate genes (TCF7L2, HHEX, KCNJ11, and ADIPOQ) related to type 2 diabetes (T2D) in an endogamous population of north India; the Aggarwal population, having 18‐clans. This endogamous population model was heavily supported by recent land mark work and we also verified the homogeneity of this population by clan‐based stratification analysis. Two SNPs (rs4506565; rs7903146) in TCF7L2 were found to be significant (p‐value = 0.00191; p‐value = 0.00179, respectively), and odds ratios of 2.1 (dominant‐model) and 2.0 (recessive‐model) respectively, were obtained for this population. The TTT haplotype in the TCF7L2 gene was significantly associated with T2D. Waist‐Hip ratio (WHR), systolic blood pressure (SBP), and age were significant covariates for increasing risk of T2D. Single‐SNP, combined‐SNPs and haplotype analysis provides clear evidence that the causal mutation is near to or within the significant haplotype (TTT) of the TCF7L2 gene. In spite of a culturally‐learned sedentary lifestyle and fat‐enriched dietary habits, WHR rather than body‐mass‐index emerged as a robust predictor of risk for T2D in this population.

Next generation sequencing in cardiomyopathy: towards personalized genomics and medicine

Next generation sequencing (NGS) is perhaps one of the most exciting advances in the field of life sciences and biomedical research in the last decade. With the availability of massive parallel sequencing, human DNA blueprint can be decoded to explore the hidden information with reduced time and cost. This technology has been used to understand the genetic aspects of various diseases including cardiomyopathies. Mutations for different cardiomyopathies have been identified and cataloging mutations on phenotypic basis are underway and are expected to lead to new discoveries that may translate to novel diagnostic, prognostic and therapeutic targets. With ease in handling NGS, cost effectiveness and fast data output, NGS is now considered as a diagnostic tool for cardiomyopathy by providing targeted gene sequencing. In addition to the number of genetic variants that are identified in cardiomyopathies, there is a need of quicker and easy way to screen multiple genes associated with the disease. In this review, an attempt has been made to explain the NGS technology, methods and applications in cardiomyopathies and their perspective in clinical practice and challenges which are to be addressed.

Neuropeptide Y gene functional polymorphism influences susceptibility to hypertension in Indian population

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.

Allelic variation and haplotype structure of the dopamine receptor gene DRD2 in nine Indian 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.

Association between Neuropeptide Y Gene Polymorphisms and Alcohol Dependence: A Case-Control Study in Two Independent Populations

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.

Population-Based Case-Control Study of DRD2 Gene Polymorphisms and Alcoholism

ABSTRACT 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.

Dementia and Cognitive Impairment in Patients With Parkinson’s Disease From India A 7-Year Prospective Study

Depression and cognitive impairment are frequent manifestations in Parkinson’s disease (PD). Although a few longitudinal studies have reported on depression and dementia in PD, there is a yet a lack of such studies in India. This 7-year longitudinal study is a hospital-based prospective case (n = 250)–control (n = 280) study. In all, 36.8% had PD with no cognitive impairment (PD-Normal), 27.2% of the patients with PD were affected by dementia (PDD), and 36% of the remaining patients with PD had mild cognitive impairment (PD-MCI) at baseline. After 7 years of evaluation, 32 new patients, 12 patients from the PD-MCI group and 9 patients from the PD-Normal group, were diagnosed with dementia. The 7-year prevalence rate for dementia was estimated to be 49.28%. In the Indian population, an early onset of dementia is noted among patients with PD, with the age of onset being less than 55 years. Patients with early-onset PDD showed depression symptoms that differed significantly from the controls of the same age-group. There was a major difference in verbal fluency, word list recall, constructional praxis and recall, word list recognition, abridged Boston Naming Test, word list memory with repetition, and Mini-Mental State Examination between PD-MCI and PDD groups. Hallucinations before baseline (odds ratio [OR] = 4.427, 95% confidence interval [CI] = 2.122-9.373), akinetic/tremor dominancy (OR = 0.380, 95%CI = 0.149-0.953), and asymmetrical disease onset (OR = 0.3285, 95%CI = 0.1576-0.685) can be considered as risk factors for patients with dementia. Patients with early-onset PD might be more prone to complex depression and dementia. As the disease progresses, akinetic-dominant PD, early hallucinations, and asymmetrical disease onset are the potential risk factors for the development of dementia in patients with PD.

Association Between the M268T Polymorphism in the Angiotensinogen Gene and Essential Hypertension in a South Indian Population

Essential hypertension is a complex multifactorial disease caused by interactions between genetic and environmental factors. It is an independent determinant of cardiovascular risk. The main aim of this study was to investigate the possible influence of angiotensinogen M268T polymorphisms on hypertension in two endogamous caste populations of South India. Systolic and diastolic blood pressure, anthropometric variables, and lipid profiles were assessed. Direct sequencing of PCR products was adopted for genotyping. This polymorphism was found to be in Hardy–Weinberg equilibrium in the patients and controls of both populations. Binary odds ratios showed significant association between the M268T polymorphism and hypertension in both populations. Multivariate analysis revealed significant differences in body mass index, chest girth, calf circumference, skinfold measurements, total cholesterol, and triglyceride levels between these genotypes in the Gavara and Vaishya populations. These data further support the hypothesis that hypertension is influenced by the AGT M268T polymorphism.

EPHX1 Gene Polymorphisms in Alcohol Dependence and their Distribution among the Indian Populations

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 χ2 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.

Genetic Affinity of the Bhil, Kol and Gond Mentioned in Epic Ramayana

Kol, Bhil and Gond are some of the ancient tribal populations known from the Ramayana, one of the Great epics of India. Though there have been studies about their affinity based on classical and haploid genetic markers, the molecular insights of their relationship with other tribal and caste populations of extant India is expected to give more clarity about the the question of continuity vs. discontinuity. In this study, we scanned >97,000 of single nucleotide polymorphisms among three major ancient tribes mentioned in Ramayana, namely Bhil, Kol and Gond. The results obtained were then compared at inter and intra population levels with neighboring and other world populations. Using various statistical methods, our analysis suggested that the genetic architecture of these tribes (Kol and Gond) was largely similar to their surrounding tribal and caste populations, while Bhil showed closer affinity with Dravidian and Austroasiatic (Munda) speaking tribes. The haplotype based analysis revealed a massive amount of genome sharing among Bhil, Kol, Gond and with other ethnic groups of South Asian descent. On the basis of genetic component sharing among different populations, we anticipate their primary founding over the indigenous Ancestral South Indian (ASI) component has prevailed in the genepool over the last several thousand years.