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1.  RAF1 mutations in childhood-onset dilated cardiomyopathy 
Nature genetics  2014;46(6):635-639.
Dilated cardiomyopathy (DCM) is a highly heterogeneous trait with sarcomeric gene mutations predominating. The cause of a significant percentage of DCM remains unknown and no gene-specific therapy is available. Based on resequencing with 513 DCM cases and 1,150 matched controls from various ethnically distinct cohorts, we discovered rare, functional RAF1 mutations in three of them (South India, North India and Japan). The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in those three cohorts. Biochemical studies showed that DCM-associated RAF1 mutants had altered kinase activity, resulting in largely unaltered ERK activation but AKT that was hyperactivated in a BRAF-dependent manner. Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by rapamycin treatment. These findings provide new mechanistic insights and potential therapeutic targets for RAF1-associated DCM and further expand the clinical spectrum of RAF1-related human disorders.
doi:10.1038/ng.2963
PMCID: PMC4049514  PMID: 24777450
2.  Propagation of pure fetal and maternal mesenchymal stromal cells from terminal chorionic villi of human term placenta 
Scientific Reports  2015;5:10054.
Long term propagation of human fetal mesenchymal stromal cells (MSC) in vitro has proven elusive due to limited availability of fetal tissue sources and lack of appropriate methodologies. Here, we have demonstrated the presence of fetal and maternal cells within the tips of terminal chorionic villi (TCV) of normal human term placenta, and we have exploited inherent differences in the adhesive and migratory properties of maternal vs. fetal cells, to establish pure MSC cultures of both cell types. The origin and purity of each culture was confirmed by X-Y chromosome-specific fluorescence in situ hybridization (FISH) and short tandem repeat (STR) genotyping. This is the first demonstration of fetal and maternal cells in the TCV of human term placenta and also of deriving pure fetal MSC cultures from them. The concomitant availability of pure cultures of adult and fetal MSC from one tissue provides a good system to compare genetic and epigenetic differences between adult and fetal MSCs; and also to generate new models of cell based therapies in regenerative medicine.
doi:10.1038/srep10054
PMCID: PMC4432313  PMID: 25975441
3.  Association of Ficolin-2 Serum Levels and FCN2 Genetic Variants with Indian Visceral Leishmaniasis 
PLoS ONE  2015;10(5):e0125940.
Background
Visceral leishmaniasis (VL), one of the neglected tropical diseases, is endemic in the Indian subcontinent. Ficolins are circulating serum proteins of the lectin complement system and involved in innate immunity.
Methods
We have estimated ficolin-2 serum levels and analyzed the functional variants of the encoding gene FCN2 in 218 cases of VL and in 225 controls from an endemic region of India.
Results
Elevated levels of serum ficolin-2 were observed in VL cases compared to the controls (adjusted P<0.0001). The genetic analysis revealed that the FCN2 structural variant +6359 C>T (p.T236M) was associated with VL (OR=2.2, 95% CI=1.23-7.25, P=0.008) and with high ficolin-2 serum levels. We also found that the FCN2*AAAC haplotype occurred more frequently among healthy controls when compared to cases (OR=0.59, 95%CI=0.37-0.94, P=0.023).
Conclusions
Our findings indicate that the FCN2 variant +6359C>T is associated with the occurrence of VL and that ficolin-2 serum levels are elevated in Leishmania infections.
doi:10.1371/journal.pone.0125940
PMCID: PMC4428791  PMID: 25965808
4.  DNA methylation analysis of phenotype specific stratified Indian population 
Background
DNA methylation and its perturbations are an established attribute to a wide spectrum of phenotypic variations and disease conditions. Indian traditional system practices personalized medicine through indigenous concept of distinctly descriptive physiological, psychological and anatomical features known as prakriti. Here we attempted to establish DNA methylation differences in these three prakriti phenotypes.
Methods
Following structured and objective measurement of 3416 subjects, whole blood DNA of 147 healthy male individuals belonging to defined prakriti (Vata, Pitta and Kapha) between the age group of 20-30years were subjected to methylated DNA immunoprecipitation (MeDIP) and microarray analysis. After data analysis, prakriti specific signatures were validated through bisulfite DNA sequencing.
Results
Differentially methylated regions in CpG islands and shores were significantly enriched in promoters/UTRs and gene body regions. Phenotypes characterized by higher metabolism (Pitta prakriti) in individuals showed distinct promoter (34) and gene body methylation (204), followed by Vata prakriti which correlates to motion showed DNA methylation in 52 promoters and 139 CpG islands and finally individuals with structural attributes (Kapha prakriti) with 23 and 19 promoters and CpG islands respectively. Bisulfite DNA sequencing of prakriti specific multiple CpG sites in promoters and 5′-UTR such as; LHX1 (Vata prakriti), SOX11 (Pitta prakriti) and CDH22 (Kapha prakriti) were validated. Kapha prakriti specific CDH22 5′-UTR CpG methylation was also found to be associated with higher body mass index (BMI).
Conclusion
Differential DNA methylation signatures in three distinct prakriti phenotypes demonstrate the epigenetic basis of Indian traditional human classification which may have relevance to personalized medicine.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0506-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0506-0
PMCID: PMC4438459  PMID: 25952924
DNA methylation; MeDIP; CpG Island; Prakriti; Ayurveda
5.  IL10 Variant g.5311A Is Associated with Visceral Leishmaniasis in Indian Population 
PLoS ONE  2015;10(5):e0124559.
Background
Visceral leishmaniasis (VL) is a multifactorial disease, where the host genetics play a significant role in determining the disease outcome. The immunological role of anti-inflammatory cytokine, Interleukin 10 (IL10), has been well-documented in parasite infections and considered as a key regulatory cytokine for VL. Although VL patients in India display high level of IL10 in blood serum, no genetic study has been conducted to assess the VL susceptibility / resistance. Therefore, the aim of this study is to investigate the role of IL10 variations in Indian VL; and to estimate the distribution of disease associated allele in diverse Indian populations.
Methodology
All the exons and exon-intron boundaries of IL10 were sequenced in 184 VL patients along with 172 ethnically matched controls from VL endemic region of India.
Result and Discussion
Our analysis revealed four variations; rs1518111 (2195 A>G, intron), rs1554286 (2607 C>T, intron), rs3024496 (4976 T>C, 3’ UTR) and rs3024498 (5311 A>G, 3’ UTR). Of these, a variant g.5311A is significantly associated with VL (χ2=18.87; p =0.00001). In silico approaches have shown that a putative micro RNA binding site (miR-4321) is lost in rs3024498 mRNA. Further, analysis of the above four variations in 1138 individuals from 34 ethnic populations, representing different social and linguistic groups who are inhabited in different geographical regions of India, showed variable frequency. Interestingly, we have found, majority of the tribal populations have low frequency of VL (‘A’ of rs3024498); and high frequency of leprosy (‘T’ of rs1554286), and Behcet’s (‘A’ of rs1518111) associated alleles, whereas these were vice versa in castes. Our findings suggest that majority of tribal populations of India carry the protected / less severe allele against VL, while risk / more severe allele for leprosy and Behcet’s disease. This study has potential implications in counseling and management of VL and other infectious diseases.
doi:10.1371/journal.pone.0124559
PMCID: PMC4420251  PMID: 25941808
6.  MTHFR 677C>T Polymorphism and the Risk of Breast Cancer: Evidence from an Original Study and Pooled Data for 28031 Cases and 31880 Controls 
PLoS ONE  2015;10(3):e0120654.
Background
Methylenetetrahydrofolate reductase (MTHFR) acts at an important metabolic point in the regulation of cellular methylation reaction. It assists in the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The latter aids in remethylation of homocysteine to de novo methionine that is required for DNA synthesis. The objective of this study was to examine the effect of MTHFR 677 C>T polymorphism on the risk of breast cancer in the Indian sub-continent.
Methods and Results
We genotyped 677 C>T locus in 1096 individuals that were classified into cases (N=588) and controls (N=508). Genotype data were analyzed using chi-square test. No significant difference was observed in the distribution of genotypes between cases and controls in north Indian (P = 0.932), south Indian (P = 0.865), and pooled data (P = 0.680). To develop a consensus regarding the impact of 677C>T polymorphism on breast cancer risk, we also conducted a meta-analysis on 28031 cases and 31880 controls that were pooled from sixty one studies. The overall summary estimate upon meta-analysis suggested no significant correlation between the 677C>T substitution and breast cancer in the dominant model (Fixed effect model: OR = 0.97, P=0.072, Random effects model: OR = 0.96, P = 0.084) or the recessive model (Fixed effect model: OR = 1.05, P = 0.089; Random effects model: OR= 1.08, P= 0.067).
Conclusion
677 C>T substitution does not affect breast cancer risk in the Indo-European and Dravidian populations of India. Analysis on pooled data further ruled out association between the 677 C>T polymorphism and breast cancer. Therefore, 677 C>T substitution does not appear to influence the risk of breast cancer.
doi:10.1371/journal.pone.0120654
PMCID: PMC4372432  PMID: 25803740
7.  Ancient human genomes suggest three ancestral populations for present-day Europeans 
Lazaridis, Iosif | Patterson, Nick | Mittnik, Alissa | Renaud, Gabriel | Mallick, Swapan | Kirsanow, Karola | Sudmant, Peter H. | Schraiber, Joshua G. | Castellano, Sergi | Lipson, Mark | Berger, Bonnie | Economou, Christos | Bollongino, Ruth | Fu, Qiaomei | Bos, Kirsten I. | Nordenfelt, Susanne | Li, Heng | de Filippo, Cesare | Prüfer, Kay | Sawyer, Susanna | Posth, Cosimo | Haak, Wolfgang | Hallgren, Fredrik | Fornander, Elin | Rohland, Nadin | Delsate, Dominique | Francken, Michael | Guinet, Jean-Michel | Wahl, Joachim | Ayodo, George | Babiker, Hamza A. | Bailliet, Graciela | Balanovska, Elena | Balanovsky, Oleg | Barrantes, Ramiro | Bedoya, Gabriel | Ben-Ami, Haim | Bene, Judit | Berrada, Fouad | Bravi, Claudio M. | Brisighelli, Francesca | Busby, George B. J. | Cali, Francesco | Churnosov, Mikhail | Cole, David E. C. | Corach, Daniel | Damba, Larissa | van Driem, George | Dryomov, Stanislav | Dugoujon, Jean-Michel | Fedorova, Sardana A. | Romero, Irene Gallego | Gubina, Marina | Hammer, Michael | Henn, Brenna M. | Hervig, Tor | Hodoglugil, Ugur | Jha, Aashish R. | Karachanak-Yankova, Sena | Khusainova, Rita | Khusnutdinova, Elza | Kittles, Rick | Kivisild, Toomas | Klitz, William | Kučinskas, Vaidutis | Kushniarevich, Alena | Laredj, Leila | Litvinov, Sergey | Loukidis, Theologos | Mahley, Robert W. | Melegh, Béla | Metspalu, Ene | Molina, Julio | Mountain, Joanna | Näkkäläjärvi, Klemetti | Nesheva, Desislava | Nyambo, Thomas | Osipova, Ludmila | Parik, Jüri | Platonov, Fedor | Posukh, Olga | Romano, Valentino | Rothhammer, Francisco | Rudan, Igor | Ruizbakiev, Ruslan | Sahakyan, Hovhannes | Sajantila, Antti | Salas, Antonio | Starikovskaya, Elena B. | Tarekegn, Ayele | Toncheva, Draga | Turdikulova, Shahlo | Uktveryte, Ingrida | Utevska, Olga | Vasquez, René | Villena, Mercedes | Voevoda, Mikhail | Winkler, Cheryl | Yepiskoposyan, Levon | Zalloua, Pierre | Zemunik, Tatijana | Cooper, Alan | Capelli, Cristian | Thomas, Mark G. | Ruiz-Linares, Andres | Tishkoff, Sarah A. | Singh, Lalji | Thangaraj, Kumarasamy | Villems, Richard | Comas, David | Sukernik, Rem | Metspalu, Mait | Meyer, Matthias | Eichler, Evan E. | Burger, Joachim | Slatkin, Montgomery | Pääbo, Svante | Kelso, Janet | Reich, David | Krause, Johannes
Nature  2014;513(7518):409-413.
We sequenced the genomes of a ~7,000 year old farmer from Germany and eight ~8,000 year old hunter-gatherers from Luxembourg and Sweden. We analyzed these and other ancient genomes1–4 with 2,345 contemporary humans to show that most present Europeans derive from at least three highly differentiated populations: West European Hunter-Gatherers (WHG), who contributed ancestry to all Europeans but not to Near Easterners; Ancient North Eurasians (ANE) related to Upper Paleolithic Siberians3, who contributed to both Europeans and Near Easterners; and Early European Farmers (EEF), who were mainly of Near Eastern origin but also harbored WHG-related ancestry. We model these populations’ deep relationships and show that EEF had ~44% ancestry from a “Basal Eurasian” population that split prior to the diversification of other non-African lineages.
doi:10.1038/nature13673
PMCID: PMC4170574  PMID: 25230663
8.  c.620C>T mutation in GATA4 is associated with congenital heart disease in South India 
BMC Medical Genetics  2015;16:7.
Background
Congenital heart diseases (CHDs) usually refer to abnormalities in the structure and/or function of the heart that arise before birth. GATA4 plays an important role in embryonic heart development, hence the aim of this study was to find the association of GATA4 mutations with CHD among the south Indian CHD patients.
Method
GATA4 gene was sequenced in 100 CHD patients (ASD, VSD, TOF and SV) and 200 controls. Functional significance of the observed GATA4 mutations was analyzed using PolyPhen, SIFT, PMut, Plink, Haploview, ESE finder 3.0 and CONSITE.
Results
We observed a total of 19 mutations, of which, one was in 5′ UTR, 10 in intronic regions, 3 in coding regions and 5 in 3′ UTR. Of the above mutations, one was associated with Atrial Septal Defect (ASD), two were found to be associated with Tetralogy of Fallot (TOF) and three (rs804280, rs4841587 and rs4841588) were strongly associated with Ventricular Septal Defect (VSD). Interestingly, one promoter mutation (−490 to 100 bp) i.e., 620 C>T (rs61277615, p-value = 0.008514), one splice junction mutation (G>A rs73203482; p-value = 9.6e-3, OR = 6.508) and one intronic mutation rs4841587 (p-value = 4.6e-3, OR = 4.758) were the most significant findings of this study. In silico analysis also proves that some of the mutations reported above are pathogenic.
Conclusion
The present study found that GATA4 genetic variations are associated with ASD, TOF and VSD in South Indian patients. In silico analysis provides further evidence that some of the observed mutations are pathogenic.
Electronic supplementary material
The online version of this article (doi:10.1186/s12881-015-0152-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12881-015-0152-7
PMCID: PMC4422155  PMID: 25928801
Congenital heart disease; GATA4; Mutation; South Indian patients; ASD; TOF; VSD
9.  Mitochondrial disorders: Challenges in diagnosis & treatment 
Mitochondrial dysfunctions are known to be responsible for a number of heterogenous clinical presentations with multi-systemic involvement. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these disorders. Despite significant progress made in the field of mitochondrial medicine during the last two decades, the molecular mechanisms underlying these disorders are not fully understood. Since the identification of first mitochondrial DNA (mtDNA) mutation in 1988, there has been an exponential rise in the identification of mtDNA and nuclear DNA mutations that are responsible for mitochondrial dysfunction and disease. Genetic complexity together with ever widening clinical spectrum associated with mitochondrial dysfunction poses a major challenge in diagnosis and treatment. Effective therapy has remained elusive till date and is mostly efficient in relieving symptoms. In this review, we discuss the important clinical and genetic features of mitochondrials disorders with special emphasis on diagnosis and treatment.
PMCID: PMC4405934  PMID: 25857492
Diagnosis; diseases; mitochondrial DNA; mutation; treatment
10.  Association of progesterone receptor gene polymorphism with male infertility and clinical outcome of ICSI 
Purpose
To investigate the association of Progesterone Receptor (PR) gene variations and male infertility
Methods
DNA extraction, PCR and sequencing of PR gene, PROGINS insertion by PCR. Association of the variations with seminal parameters and outcomes of ICSI.
Results
Four known SNPs in the PR gene were identified in the study of which three (rs3740753, rs1042838, rs104283) were co-inherited and in complete linkage disequilibrium with the PROGINS Alu insertion. There were no differences in their frequencies between fertile and infertile males. The rs2020880 was found at a very low frequency only in the controls but not in the infertile subjects. The sperm counts, fertilization rate, embryo quality or pregnancy rates were not different in individuals with or without PROGINS allele.
Conclusion
PR gene alterations are not associated with male infertility or ICSI outcome.
Electronic supplementary material
The online version of this article (doi:10.1007/s10815-013-0074-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s10815-013-0074-2
PMCID: PMC3800537  PMID: 23934021
Progesterone receptor; Polymorphism; PROGINS; Male infertility; ICSI; Azoospermia; Sperm counts
11.  Reduced prevalence of placental malaria in primiparae with blood group O 
Malaria Journal  2014;13:289.
Background
Blood group O protects African children against severe malaria and has reached high prevalence in malarious regions. However, its role in malaria in pregnancy is ambiguous. In 839 delivering Ghanaian women, associations of ABO blood groups with Plasmodium falciparum infection were examined.
Methods
Plasmodium falciparum infection was diagnosed in placental blood samples by microscopy and PCR assays. Present or past infection was defined as the detection of parasitaemia or haemozoin by microscopy, or a positive PCR result. Blood groups were inferred from genotyping rs8176719 (indicating the O allele) and rs8176746/rs8176747 (distinguishing the B allele from the A allele).
Results
The majority of women had blood group O (55.4%); present or past P. falciparum infection was seen in 62.3% of all women. Among multiparae, the blood groups had no influence on P. falciparum infection. In contrast, primiparae with blood group O had significantly less present or past infection than women with non-O blood groups (61.5 vs 76.2%, P = 0.007). In multivariate analysis, the odds of present or past placental P. falciparum infection were reduced by 45% in blood group O primiparae (aOR, 0.55 [95% CI, 0.33–0.94]).
Conclusions
The present study shows a clear protective effect of blood group O against malaria in primiparae. This accords with findings in severe malaria and in vitro results. The data underline the relevance of host genetic protection among primiparae, i.e. the high-risk group for malaria in pregnancy, and contribute to the understanding of high O allele frequencies in Africa.
doi:10.1186/1475-2875-13-289
PMCID: PMC4119177  PMID: 25066505
12.  Novel TCAP Mutation c.32C>A Causing Limb Girdle Muscular Dystrophy 2G 
PLoS ONE  2014;9(7):e102763.
TCAP encoded telethonin is a 19 kDa protein, which plays an important role in anchoring titin in Z disc of the sarcomere, and is known to cause LGMD2G, a rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. A total of 300 individuals with ARLGMD were recruited for this study. Among these we identified 8 clinically well characterised LGMD2G cases from 7 unrelated Dravidian families. Clinical examination revealed predominantly proximo - distal form of weakness, scapular winging, muscle atrophy, calf hypertrophy and foot drop, immunoblot showed either complete absence or severe reduction of telethonin. Genetic analysis revealed a novel nonsense homozygous mutation c.32C>A, p.(Ser11*) in three patients of a consanguineous family and an 8 bp homozygous duplication c.26_33dupAGGTGTCG, p.(Arg12fs31*) in another patient. Both mutations possibly lead to truncated protein or nonsense mediated decay. We could not find any functionally significant TCAP mutation in the remaining 6 samples, except for two other polymorphisms, c.453A>C, p.( = ) and c.-178G>T, which were found in cases and controls. This is the first report from India to demonstrate TCAP association with LGMD2G.
doi:10.1371/journal.pone.0102763
PMCID: PMC4108395  PMID: 25055047
13.  A Novel Arginine to Tryptophan (R144W) Mutation in Troponin T (cTnT) Gene in an Indian Multigenerational Family with Dilated Cardiomyopathy (FDCM) 
PLoS ONE  2014;9(7):e101451.
Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in sarcomeric protein genes have been associated with this disease. Our aim in the present study is to investigate the genetic variations in Troponin T (cTnT) gene and its association with dilated cardiomyopathy (DCM) in south-Indian patients. Analyses of all the exons and exon-intron boundaries of cTnT in 147 DCM and in 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL; of which, polymorphic SNPs were compared with the HapMap population data. Interestingly, a novel R144W mutation, that substitutes polar-neutral tryptophan for a highly conserved basic arginine in cTnT, altering the charge drastically, was identified in a DCM, with a family history of sudden-cardiac death (SCD). This mutation was found within the tropomyosin (TPM1) binding domain, and was evolutionarily conserved across species, therefore it is expected to have a significant impact on the structure and function of the protein. Family studies had revealed that the R144W is co-segregating with disease in the family as an autosomal dominant trait, but it was completely absent in 207 healthy controls and in 162 previously studied HCM patients. Further screening of the proband and three of his family members (positive for R144W mutant) with eight other genes β-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3, did not reveal any disease causing mutation, proposing the absence of compound heterozygosity. Therefore, we strongly suggest that the novel R144W unique/private mutant identified in this study is associated with FDCM. This is furthermore signifying the unique genetic architecture of Indian population.
doi:10.1371/journal.pone.0101451
PMCID: PMC4081629  PMID: 24992688
14.  MBL2 Variations and Malaria Susceptibility in Indian Populations 
Infection and Immunity  2014;82(1):52-61.
Human mannose-binding lectin (MBL) encoded by the MBL2 gene is a pattern recognition protein and has been associated with many infectious diseases, including malaria. We sought to investigate the contribution of functional MBL2 gene variations to Plasmodium falciparum malaria in well-defined cases and in matched controls. We resequenced the 8.7 kb of the entire MBL2 gene in 434 individuals clinically classified with malaria from regions of India where malaria is endemic. The study cohort included 176 patients with severe malaria, 101 patients with mild malaria, and 157 ethnically matched asymptomatic individuals. In addition, 830 individuals from 32 socially, linguistically, and geographically diverse endogamous populations of India were investigated for the distribution of functional MBL2 variants. The MBL2 −221C (X) allelic variant is associated with increased risk of malaria (mild malaria odds ratio [OR] = 1.9, corrected P value [PCorr] = 0.0036; severe malaria OR = 1.6, PCorr = 0.02). The exon1 variants MBL2*B (severe malaria OR = 2.1, PCorr = 0.036; mild versus severe malaria OR = 2.5, PCorr = 0.039) and MBL2*C (mild versus severe malaria OR = 5.4, PCorr = 0.045) increased the odds of having malaria. The exon1 MBL2*D/*B/*C variant increased the risk for severe malaria (OR = 3.4, PCorr = 0.000045). The frequencies of low MBL haplotypes were significantly higher in severe malaria (14.2%) compared to mild malaria (7.9%) and asymptomatic (3.8%). The MBL2*LYPA haplotypes confer protection, whereas MBL2*LXPA increases the malaria risk. Our findings in Indian populations demonstrate that MBL2 functional variants are strongly associated with malaria and infection severity.
doi:10.1128/IAI.01041-13
PMCID: PMC3911836  PMID: 24126531
15.  Determinants of Prakriti, the Human Constitution Types of Indian Traditional Medicine and its Correlation with Contemporary Science 
Background:
Constitutional type of an individual or prakriti is the basic clinical denominator in Ayurveda, which defines physical, physiological, and psychological traits of an individual and is the template for individualized diet, lifestyle counseling, and treatment. The large number of phenotype description by prakriti determination is based on the knowledge and experience of the assessor, and hence subject to inherent variations and interpretations.
Objective:
In this study we have attempted to relate dominant prakriti attribute to body mass index (BMI) of individuals by assessing an acceptable tool to provide the quantitative measure to the currently qualitative ayurvedic prakriti determination.
Materials and Methods:
The study is cross sectional, multicentered, and prakriti assessment of a total of 3416 subjects was undertaken. Healthy male, nonsmoking, nonalcoholic volunteers between the age group of 20-30 were screened for their prakriti after obtaining written consent to participate in the study. The prakriti was determined on the phenotype description of ayurvedic texts and simultaneously by the use of a computer-aided prakriti assessment tool. Kappa statistical analysis was employed to validate the prakriti assessment and Chi-square, Cramer's V test to determine the relatedness in the dominant prakriti to various attributes.
Results:
We found 80% concordance between ayurvedic physician and software in predicting the prakriti of an individual. The kappa value of 0.77 showed moderate agreement in prakriti assessment. We observed a significant correlations of dominant prakriti to place of birth and BMI with Chi-square, P < 0.01 (Cramer's V-value of 0.156 and 0.368, respectively).
Conclusion:
The present study attempts to integrate knowledge of traditional ayurvedic concepts with the contemporary science. We have demonstrated analysis of prakriti classification and its association with BMI and place of birth with the implications to one of the ways for human classification.
doi:10.4103/0975-9476.140478
PMCID: PMC4204287  PMID: 25336848
Ayusoft; body mass index; place of birth; Prakriti
17.  A novel insertion-induced frameshift mutation of the androgen receptor gene in a patient with primary amenorrhea☆ 
Meta Gene  2013;2:11-15.
Objective
To report a novel single nucleotide insertion mutation, and present the clinical, genetic, biochemical findings in a patient with primary amenorrhea.
Methods
Chromosomal analysis was performed by harvesting lymphocytes from peripheral blood sample. Hormonal analysis was performed from the serum. After genomic DNA extraction from peripheral blood leukocytes the coding regions and corresponding exon–intron boundaries of sex-determining region Y (SRY) gene and androgen receptor (AR) gene were amplified by PCR and subjected to direct sequencing.
Results
In the patient with a karyotype 46,XX, we identified a novel single nucleotide insertion mutation of the nucleotide G at position 2369 (GenBank accession number HM010955), resulting in amino acid interchange cysteine to tryptophan at codon 669 in exon 4 [Cys669Trp] (GenBank Protein_id ADF47187).
Conclusions
We report a novel single nucleotide insertion mutation in exon 4 region of the AR gene. The nature of the mutation presented in the patient is in the ligand-binding domain (LBD) of the AR gene. This insertion mutation was predicted to produce frame shift mutation and resulted in truncated form of the AR protein, implicating it in the phenotype observed with primary amenorrhea.
Highlights
•AR is a member of the steroid receptor superfamily.•AR gene was screened in a patient with primary amenorrhea by direct PCR sequencing.•A novel insertion mutation (c.2369_2370insG, p.Cys669TrpfsX12) was identified.•This causes frame shift mutation resulting in truncated form of the AR protein.•The finding further enriched the AR mutation spectrum.
doi:10.1016/j.mgene.2013.10.011
PMCID: PMC4287795  PMID: 25606384
AR, androgen receptor; SRY, sex-determining region Y; PCR, polymerase chain reaction; LBD, ligand-binding domain.; AR gene; Primary amenorrhea; Novel mutation
18.  Correction: Androgen Receptor CAG Repeats Length Polymorphism and the Risk of Polycystic Ovarian Syndrome (PCOS) 
PLoS ONE  2013;8(11):10.1371/annotation/61e2a995-4084-465a-9e4e-0b71d02f8f31.
doi:10.1371/annotation/61e2a995-4084-465a-9e4e-0b71d02f8f31
PMCID: PMC3832676
19.  The Light Skin Allele of SLC24A5 in South Asians and Europeans Shares Identity by Descent 
PLoS Genetics  2013;9(11):e1003912.
Skin pigmentation is one of the most variable phenotypic traits in humans. A non-synonymous substitution (rs1426654) in the third exon of SLC24A5 accounts for lighter skin in Europeans but not in East Asians. A previous genome-wide association study carried out in a heterogeneous sample of UK immigrants of South Asian descent suggested that this gene also contributes significantly to skin pigmentation variation among South Asians. In the present study, we have quantitatively assessed skin pigmentation for a largely homogeneous cohort of 1228 individuals from the Southern region of the Indian subcontinent. Our data confirm significant association of rs1426654 SNP with skin pigmentation, explaining about 27% of total phenotypic variation in the cohort studied. Our extensive survey of the polymorphism in 1573 individuals from 54 ethnic populations across the Indian subcontinent reveals wide presence of the derived-A allele, although the frequencies vary substantially among populations. We also show that the geospatial pattern of this allele is complex, but most importantly, reflects strong influence of language, geography and demographic history of the populations. Sequencing 11.74 kb of SLC24A5 in 95 individuals worldwide reveals that the rs1426654-A alleles in South Asian and West Eurasian populations are monophyletic and occur on the background of a common haplotype that is characterized by low genetic diversity. We date the coalescence of the light skin associated allele at 22–28 KYA. Both our sequence and genome-wide genotype data confirm that this gene has been a target for positive selection among Europeans. However, the latter also shows additional evidence of selection in populations of the Middle East, Central Asia, Pakistan and North India but not in South India.
Author Summary
Human skin color is one of the most visible aspects of human diversity. The genetic basis of pigmentation in Europeans has been understood to some extent, but our knowledge about South Asians has been restricted to a handful of studies. It has been suggested that a single nucleotide difference in SLC24A5 accounts for 25–38% European-African pigmentation differences and correlates with lighter skin. This genetic variant has also been associated with skin color variation among South Asians living in the UK. Here, we report a study based on a homogenous cohort of South India. Our results confirm that SLC24A5 plays a key role in pigmentation diversity of South Asians. Country-wide screening of the variant reveals that the light skin associated allele is widespread in the Indian subcontinent and its complex patterning is shaped by a combination of processes involving selection and demographic history of the populations. By studying the variation of SLC24A5 sequences among a diverse set of individuals, we show that the light skin associated allele in South Asians is identical by descent to that found in Europeans. Our study also provides new insights into positive selection acting on the gene and the evolutionary history of light skin in humans.
doi:10.1371/journal.pgen.1003912
PMCID: PMC3820762  PMID: 24244186
20.  Strong Impact of TGF-β1 Gene Polymorphisms on Breast Cancer Risk in Indian Women: A Case-Control and Population-Based Study 
PLoS ONE  2013;8(10):e75979.
Introduction
TGF-β1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-β1 signaling in breast cancer progression is well documented. Some TGF-β1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear.
Methods
We analyzed 1222 samples in a candidate gene-based genetic association study on two distantly located and ethnically divergent case-control groups of Indian women, followed by a population-based genetic epidemiology study analyzing these polymorphisms in other Indian populations. The c.29C>T (Pro10Leu, rs1982073 or rs1800470) and c.74G>C (Arg25Pro, rs1800471) polymorphisms in the TGF-β1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-β1 were measured by ELISA.
Results
c.29C>T substitution increased breast cancer risk, irrespective of ethnicity and menopausal status. On the other hand, c.74G>C substitution reduced breast cancer risk significantly in the north Indian group (p = 0.0005) and only in the pre-menopausal women. The protective effect of c.74G>C polymorphism may be ethnicity-specific, as no association was seen in south Indian group. The polymorphic status of c.29C>T was comparable among Indo-Europeans, Dravidians, and Tibeto-Burmans. Interestingly, we found that Tibeto-Burmans lack polymorphism at c.74G>C locus as true for the Chinese populations. However, the Brahmins of Nepal (Indo-Europeans) showed polymorphism in 2.08% of alleles. Mean TGF-β1 was significantly elevated in patients in comparison to controls (p<0.001).
Conclusion
c.29C>T and c.74G>C polymorphisms in the TGF-β1 gene significantly affect breast cancer risk, which correlates with elevated TGF-β1 level in the patients. The c.29C>T locus is polymorphic across ethnically different populations, but c.74G>C locus is monomorphic in Tibeto-Burmans and polymorphic in other Indian populations.
doi:10.1371/journal.pone.0075979
PMCID: PMC3798290  PMID: 24146803
21.  Genetic Structure of Tibeto-Burman Populations of Bangladesh: Evaluating the Gene Flow along the Sides of Bay-of-Bengal 
PLoS ONE  2013;8(10):e75064.
Human settlement and migrations along sides of Bay-of-Bengal have played a vital role in shaping the genetic landscape of Bangladesh, Eastern India and Southeast Asia. Bangladesh and Northeast India form the vital land bridge between the South and Southeast Asia. To reconstruct the population history of this region and to see whether this diverse region geographically acted as a corridor or barrier for human interaction between South Asia and Southeast Asia, we, for the first time analyzed high resolution uniparental (mtDNA and Y chromosome) and biparental autosomal genetic markers among aboriginal Bangladesh tribes currently speaking Tibeto-Burman language. All the three studied populations; Chakma, Marma and Tripura from Bangladesh showed strikingly high homogeneity among themselves and strong affinities to Northeast Indian Tibeto-Burman groups. However, they show substantially higher molecular diversity than Northeast Indian populations. Unlike Austroasiatic (Munda) speakers of India, we observed equal role of both males and females in shaping the Tibeto-Burman expansion in Southern Asia. Moreover, it is noteworthy that in admixture proportion, TB populations of Bangladesh carry substantially higher mainland Indian ancestry component than Northeast Indian Tibeto-Burmans. Largely similar expansion ages of two major paternal haplogroups (O2a and O3a3c), suggested that they arose before the differentiation of any language group and approximately at the same time. Contrary to the scenario proposed for colonization of Northeast India as male founder effect that occurred within the past 4,000 years, we suggest a significantly deep colonization of this region. Overall, our extensive analysis revealed that the population history of South Asian Tibeto-Burman speakers is more complex than it was suggested before.
doi:10.1371/journal.pone.0075064
PMCID: PMC3794028  PMID: 24130682
22.  Androgen Receptor CAG Repeats Length Polymorphism and the Risk of Polycystic Ovarian Syndrome (PCOS) 
PLoS ONE  2013;8(10):e75709.
Objective
Polycystic ovarian syndrome (PCOS) refers to an inheritable androgen excess disorder characterized by multiple small follicles located at the ovarian periphery. Hyperandrogenism in PCOS, and inverse correlation between androgen receptor (AR) CAG numbers and AR function, led us to hypothesize that CAG length variations may affect PCOS risk.
Methods
CAG repeat region of 169 patients recruited following strictly defined Rotterdam (2003) inclusion criteria and that of 175 ethnically similar control samples, were analyzed. We also conducted a meta-analysis on the data taken from published studies, to generate a pooled estimate on 2194 cases and 2242 controls.
Results
CAG bi-allelic mean length was between 8.5 and 24.5 (mean = 17.43, SD = 2.43) repeats in the controls and between 11 and 24 (mean = 17.39, SD = 2.29) repeats in the cases, without any significant difference between the two groups. Further, comparison of bi-allelic mean and its frequency distribution in three categories (short, moderate and long alleles) did not show any significant difference between controls and various case subgroups. Frequency distribution of bi-allelic mean in two categories (extreme and moderate alleles) showed over-representation of extreme sized alleles in the cases with marginally significant value (50.3% vs. 61.5%, χ2 = 4.41; P = 0.036), which turned insignificant upon applying Bonferroni correction for multiple comparisons. X-chromosome inactivation analysis showed no significant difference in the inactivation pattern of CAG alleles or in the comparison of weighed bi-allelic mean between cases and controls. Meta-analysis also showed no significant correlation between CAG length and PCOS risk, except a minor over-representation of short CAG alleles in the cases.
Conclusion
CAG bi-allelic mean length did not differ between controls and cases/case sub-groups nor did the allele distribution. Over-representation of short/extreme-sized alleles in the cases may be a chance finding without any true association with PCOS risk.
doi:10.1371/journal.pone.0075709
PMCID: PMC3792992  PMID: 24116069
23.  Variations in ncRNA gene LOC284889 and MIF-794CATT repeats are associated with malaria susceptibility in Indian populations 
Malaria Journal  2013;12:345.
Background
There are increasing evidences on the role of non-coding RNA (ncRNA) as key regulator of cellular homeostasis. LOC284889 is an uncharacterized ncRNA gene on reverse strand to MIF mapped to 22q11.23. MIF, a lymphokine, regulates innate immune response by up-regulating the expression of TLR4, suppressing the p53 activity and has been shown to be involved in malaria pathogenesis.
Methods
In this study, the possible effect of MIF variations on malaria susceptibility was investigated by re-sequencing the complete MIF gene along with 1 kb each of 5′ and 3′ region in 425 individuals from malaria endemic regions of the Orissa and Chhattisgarh states of India. The subjects comprised of 160 cases of severe malaria, 101 of mild malaria and 164 ethnically matched asymptomatic controls. Data were statistically compared between cases and controls for their possible association with Plasmodium falciparum malarial outcome.
Results
It is the first study, which shows that the allele A (rs34383331T > A) in ncRNA is significantly associated with increased risk to P. falciparum malaria [severe: OR = 2.08, p = 0.002 and mild: OR = 2.09, P = 0.005]. In addition, it has been observed that the higher MIF-794CATT repeats (>5) increases malaria risk (OR = 1.61, p = 0.01). Further, diplotype (MIF-794CATT and rs34383331T > A) 5 T confers protection to severe malaria (OR = 0.55, p = 0.002) while 6A (OR = 3.07, p = 0.001) increases malaria risk.
Conclusions
These findings support the involvement of ncRNA in malarial pathogenesis and further emphasize the complex genetic regulation of malaria outcome. In addition, the study shows that the higher MIF-794CATT repeats (>5) is a risk factor for severe malaria. The study would help in identifying people who are at higher risk to malaria and adapt strategies for prevention and treatment.
doi:10.1186/1475-2875-12-345
PMCID: PMC3849407  PMID: 24066864
Malaria; MIF; Non-coding RNA; Polymorphism; Indian populations; Diplotype
24.  Novel mutations of KCNQ1 in Long QT syndrome 
Indian Heart Journal  2013;65(5):552-560.
Background
Autosomal recessive Long QT syndrome is characterized by prolonged QTc along with congenital bilateral deafness depends on mutations in K+ channel genes. A family of a Long QT syndrome proband from India has been identified with novel indel variations.
Methods
The molecular study of the proband revealed 4 novel indel variations in KCNQ1. In-silico analysis revealed the intronic variations has led to a change in the secondary structure of mRNA and splice site variations. The exonic variations leads to frameshift mutations. DNA analysis of the available family members revealed a carrier status.
Results and Conclusion
It is thus predicted that the variations may lead to a change in the position of the splicing enhancer/inhibitor in KCNQ1 leading to the formation of a truncated S2–S3 fragment of KCNQ1 transmembrane protein in cardiac cells as well as epithelial cells of inner ear leading to deafness and aberrant repolarization causing prolonged QTc.
doi:10.1016/j.ihj.2013.08.025
PMCID: PMC3861163  PMID: 24206879
Long QT syndrome; JLN syndrome; 3D KCNQ1 structure; Novel mutations; Family study
25.  LRRK2 and RIPK2 Variants in the NOD 2-Mediated Signaling Pathway Are Associated with Susceptibility to Mycobacterium leprae in Indian Populations 
PLoS ONE  2013;8(8):e73103.
In recent years, genome wide association studies have discovered a large number of gene loci that play a functional role in innate and adaptive immune pathways associated with leprosy susceptibility. The immunological control of intracellular bacteria M. leprae is modulated by NOD2-mediated signaling of Th1 responses. In this study, we investigated 211 clinically classified leprosy patients and 230 ethnically matched controls in Indian population by genotyping four variants in NOD2 (rs9302752A/G), LRRK2 (rs1873613A/G), RIPK2 (rs40457A/G and rs42490G/A). The LRRK2 locus is associated with leprosy outcome. The LRRK2 rs1873613A minor allele and respective rs1873613AA genotypes were significantly associated with an increased risk whereas the LRRK2 rs1873613G major allele and rs1873613GG genotypes confer protection in paucibacillary and leprosy patients. The reconstructed GA haplotypes from RIPK2 rs40457A/G and rs42490G/A variants was observed to contribute towards increased risk whereas haplotypes AA was observed to confer protective role. Our results indicate that a possible shared mechanisms underlying the development of these two clinical forms of the disease as hypothesized. Our findings confirm and validates the role of gene variants involved in NOD2-mediated signalling pathways that play a role in immunological control of intracellular bacteria M. leprae.
doi:10.1371/journal.pone.0073103
PMCID: PMC3756038  PMID: 24015287

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