Abstract: 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.
Abstract: 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.
Abstract: In b-thalassemia, point mutations in the b-globin gene are largely responsible for either decreased or no b-globin synthesis. The b-globin gene has three exons and two introns. The molecular characterization of b-thalassemia is absolutely necessary for carrier screening, for genetic counseling, and to offer prenatal diagnosis. The objective of the present study was to identify the rare mutations in b-globin gene of b-thalassemia patients. We have sequenced the entire b-globin gene in 36 clinically identified thalassemia patients from the Karnataka region using polymerase chain reaction and sequencing. Our analysis revealed 11 b-thalassemia variants. The most common being IVSII-16 G> C, IVSI-5G > C, IVSII-74 T > G, codon 3 (T > C), and Poly A site (T > C). In addition, we have also documented a novel deletion at codon 6 (-CT) (HBB:c.16delCT). These data are useful in future molecular screening of the population for implementing a thalassemia prevention and control program. Further it is found that family studies and comprehensive hematological analyses would provide useful insights for accurate molecular diagnosis of thalassemia phenotype and offers an interesting subject for further investigations in the Indian populations.
Abstract: BACKGROUND: Apelin, which is a newly identified adipokine, is related to obesity and insulin resistance. A positive correlation between plasma apelin concentrations and obesity traits was reported. OBJECTIVE: We tested associations between apelin gene (APLN) polymorphisms, BMI, and waist circumference (WC) and compared APLN expression levels in cells of different genotypes. DESIGN: Four tagging single nucleotide polymorphisms (SNPs) and one promoter SNP were genotyped in 1627 Chinese subjects. Because APLN was located on the chromosome X, statistical analyses were conducted in a sex-specific manner. Adipocytes of different genotypes were derived from the omental fat tissue of 10 women. We treated the primary adipocytes with high glucose plus insulin because of a close relation between insulin resistance and obesity. RESULTS: SNP rs3115757 was significantly associated with BMI and WC in women. Compared with the CG or GG genotype, the CC genotype had an OR of 2.07 (95% CI: 1.23, 3.49) for having a high WC (P = 0.006) and an OR of 2.29 (95% CI: 1.25, 4.19) for having a BMI (in kg/m(2)) ≥27 (P = 0.007). None of the SNPs was associated with BMI or WC in men. In adipocytes that carried the CC genotype of rs3115757, APLN messenger RNA levels and protein concentrations were higher in cells treated with high glucose plus insulin than in those with normal glucose. There was no difference between the 2 conditions in adipocytes of the CG or GG genotype. CONCLUSION: Both association and functional studies suggested that APLN polymorphisms were associated with risks of obesity phenotypes.
Abstract: Cleft of the lip and palate (CL/P) are generally divided in to two groups, isolated cleft palate and cleft with or without cleft palate representing a heterogeneous group of disorders affecting the upper lip and the roof
the mouth. Non"syndromic cleft lip and palate incidence is 1 in 700 to 1000 live babies with ethnic and geographic variations. Various independent association and linkage studies using different populations have identified several loci. Numerous genes have been reported in studies demonstration associations and/or linkage of the cleft lip and palate phenotypes to alleles of microsatellite markers and single nucleotide polymorphisms within specific genes that regulate transcription factor, growth factor, cell signalling and detoxification metabolisms. Currently, efforts are focussed to identify the genes and genetic variations within the numerous candidate genes that have been found to associate with the expression of the orofacial cleft phenotype. In conclusion, the genetic basis of CL/P is still contentious because of genetic complexity of clefting.
Abstract: As genetic variation is thought to contribute to the etiology of oral cancer, microsomal epoxide hydrolase (EPHX1) was chosen as a candidate gene. This study thus sought to investigate possible genetic associations between the rs1051740, rs2292566, and rs2234922 polymorphisms of EPHX1 and oral cancer. Oral cancer patients (n=157) and healthy control subjects (n=132) were screened for the genotypes using TaqMan allelic discrimination. The associations between genotypes, alleles, and haplotypes of the three mutations and oral cancer were then analyzed using a case-control study. All the three single-nucleotide polymorphisms were polymorphic, with minor allele frequencies of 0.368, 0.249, and 0.232, respectively, for rs1051740, rs2292566, and rs2234922. None of the polymorphic sites deviated from Hardy-Weinberg equilibrium. There were no significant differences in genotype or allele frequencies of three single-nucleotide polymorphisms between controls and cases with oral cancer. Of the three studied polymorphisms, two were in strong linkage disequilibrium and formed one haplotype block. None of the haplotypes showed significant association with oral cancer. EPHX1 gene polymorphisms and haplotypes were not involved in the susceptibility to oral cancer in South Indian subjects.
Abstract: Background: Diabetes mellitus is characterized by high levels of blood glucose, late onset of disease and associated with serious complications. Genetic and environmental risk factors are known to exist and the importance of elucidating these risk factors in different populations will be of importance in view of the ultimate goal of personalized medicine. The objective was to assess the impact of risk factors such as Body Mass Index (BMI), Waist Circumference (WC), and Waist to Hip Ratio (WHR) on diabetic and control subjects using statistical tools in a specific geographical category of Indian population.
Methods: 92 diabetic patients and 123 controls living in urban areas of Nagpur city, Maharashtra, India, were selected for a case control study. BMI, WC, WHR, fasting glucose, blood pressure (systolic and diastolic) and skinfold thickness at four points were assessed. For logical interpretation, the data have been subjected to statistical analysis such as risk ratio, odds ratio and chi square. Multivariate regression analysis was carried out to adjust for age and sex.
Results: The plasma glucose, HDL cholesterol and Waist to hip ratio are significant in between control and diabetes subjects even after adjusting to age and sex.
Conclusion: Comparison of diabetic and control showed that the central obesity (WHR) and HDL were most important risk factors for type 2 diabetes in the studied population.
Abstract: Parkinson’s disease (PD) is the second most common progressive neurodegenerative brain disorder after Alzheimer’s disease. Due to the complex etiology of PD, there is possibility that single nucleotide polymorphisms (SNP) in PARKIN gene could be associated with the disease and lead to the pathogenesis by genoenvironmental interactions. Role of PARKIN polymorphisms as risk factors varies in different populations among various ethnic groups. Indian populations, known for their rich diversity, are not included in the genotyping of single nucleotide polymorphisms in the global survey for all the genes associated with PD. Further detailed study in this field will give a greater insight to analyze the haplotypic and Linakage Disequilibrium (LD) and decipher the pathogenesis of PD patterns in this region. A total of 1000 individuals belonging to ten ethnic populations of India were included in the present study. Five PARKIN gene polymorphisms (rs1801474, rs72480421, rs1801582, rs1801334 and rs35125035) were screened by PCR and sequencing. The present study shows that the rs72480421 (His200Gln) is monomorphic for all populations. Five major haplotypes accounted for almost all chromosomes (90-98%) in all populations studied. LD was more fragmented across PARKIN locus in all populations. The haplotype diversity and the fragmented LD across PARKIN gene in all populations of the present study suggest the existence of frequent recombination within the large introns of the PARKIN gene.
Abstract: Insulin resistance plays a major role in the pathogenesis of the metabolic syndrome. Inflammation is the leading cause of insulin resistance, and interleukin 10 (IL-10) is one of the anti-inflammatory cytokines. We conducted a case-control study to investigate the association between the IL-10 polymorphisms and the metabolic syndrome.
Abstract: 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.
Abstract: BACKGROUND: Orofacial clefts (OFCs) are one of the most common birth defects in humans. Maternal use of folate antagonists including dihydrofolate reductase inhibitors has been associated with a higher risk of OFCs thus suggesting that folate-related metabolism and associated genes may be involved in pathogenesis of OFC. The association between folate intake and risk of OFCs however is inconsistent. OBJECTIVE: To review the published evidence that polymorphisms in genes that affect folate metabolism are associated with an increased risk of OFCs. METHODS: We reviewed articles published up until October 2010, on polymorphisms of genes related to folate and homocysteine metabolism and their associations with OFCs. Articles were identified via Medline searches. CONCLUSIONS: No consistent evidence emerged of a strong association between risk of OFCs and any known gene related to folate metabolism. Further, recent genome-wide association studies have not identified associations between OFCs and folate-related genes. Further studies are warranted to determine whether gene-environment interactions, including gene-nutrient interactions and epigenetic modifications of genes affect the risk of OFCs.
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.
Abstract: 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.
Abstract: 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.
Abstract: Genetic stock structure analysis of two seahorse species from the south east and south west coasts of India (37 samples of Hippocampus kuda and 39 samples of Hippocampus trimaculatus from Kollam (Kerala) and Mandapam (Tamil Nadu)) was carried out through sequence variation analysis of a 350 bp cytochrome b fragment of mitochondrial DNA. This was taken up to support the breeding and restocking programme of these species in natural habitats for conservation purpose. The occurrence of strong genetic subdivision among the samples, detected by the analysis of molecular variance (AMOVA), and significant ΦST values indicated that stocks of both the species in the two Indian coasts are distinct. The findings of the present study have important implications for conservation and management of these two species and we recommend stock-specific, breeding assisted sea-ranching programme for H. kuda and H. trimaculatus along the Indian coasts.
Abstract: Nonsyndromic cleft lip and palate is a complex genetic disorder with variable phenotype, largely attributed to the interactions of the environment and multiple genes, each potentially having certain effects. Numerous genes have been reported in studies demonstrating associations and/or linkage of the cleft lip and palate phenotypes to alleles of microsatellite markers and single nucleotide polymorphisms within specific genes that regulate transcription factors, growth factors, cell signalling and detoxification metabolisms. Although the studies reporting these observations are compelling, most of them lack statistical power. This review compiles the evidence that supports linkage and associations to the various genetic loci and candidate genes. Whereas significant progress has been made in the field of cleft lip and palate genetics in the past decade, the role of the genes and genetic variations within the numerous candidate genes that have been found to associate with the expression of the orofacial cleft phenotype remain to be determined.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: NPY is a 36-aminoacid peptide expressed in several areas of the nervous system. Neuropeptide Y (NPY) receptors represent a widely diffused system that is involved in the regulation of multiple biological functions. The human NPY gene is located in chromosome 7. The functional significance of coding Leu7Pro polymorphism in the signal peptide of preproNPY is known. Six hundred and fifty four individuals of 14 ethnic Indian populations were screened for three mutations in the NPY gene, including Leu7Pro. We found that the Pro7 frequencies among the studied populations were much higher than in previous studies from other parts of the world. The highest allele frequency of Pro7 was detected in the Kota population in the Nilgiri Hill region of south India, and this may reflect a founder event in the past or genetic drift. All populations followed the Hardy-Weinberg equilibrium for the assayed markers. A total of five haplotypes were observed, only two of which were found to occur with a high frequency in all populations. No linkage disequilibrium (LD) was observed across the tested alleles in any population with the exception of Leu7Pro and Ser50Ser in the Badaga population (chi(2) = 13.969; p = 0.0001).
Abstract: Aldehyde dehydrogenase-2 (ALDH2) degrades acetaldehyde metabolized from ethanol. Its encoding gene ALDH2 has a functional polymorphism, ALDH2 Glu487Lys associated with low enzyme activity.
Abstract: 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.
Abstract: 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.
