Search

Background: Adolescent idiopathic scoliosis (AIS) is a common structural deformity of the spine affecting adolescent individuals globally. The disorder is polygenic and is accompanied by the association of various genetic loci. Genetic studies in Chinese and Japanese populations have shown the association of genetic variants of SOX9 with AIS curve severity. However, no genetic study evaluating the association of SRY-Box Transcription Factor 9 (SOX9) variants with AIS predisposition has been conducted in any Indian population. Thus, we aimed to investigate the association of the genetic variants of the SOX9 along with 0.88 Mb upstream region with AIS susceptibility in the population of Northwest India. Methods: In total, 113 AIS cases and 500 non-AIS controls were recruited from the population of Northwest India in the study and screened for 155 genetic variants across the SOX9 gene and 0.88 Mb upstream region of the gene using Global Screening Array-24 v3.0 chip (Illumina). The statistical significance of the Bonferroni threshold was set at 0.000322. Result: The results showed the association of 11 newly identified variants; rs9302936, rs7210997, rs77736349, rs12940821, rs9302937, rs77447012, rs8071904, rs74898711, rs9900249, rs2430514, and rs1042667 with the AIS susceptibility in the studied population. Only one variant, rs2430514, was inversely associated with AIS in the population, while the ten variants were associated with the AIS risk. Moreover, 47 variants clustered in the gene desert region of the SOX9 gene were associated at a p-value ≤ 0.05. Conclusion: The present study is the first to demonstrate the association of SOX9 enhancer locus variants with AIS in any South Asian Indian population. The results are interesting as rs1042667, a 3' untranslated region (UTR) variant in the exon 3 and upstream variants of the SOX9 gene, were associated with AIS susceptibility in the Northwest Indian population. This provides evidence that the variants in the enhancer region of SOX9 might regulate its gene expression, thus leading to AIS pathology and might act as an important gene for AIS susceptibility. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a multisystemic hereditary disorder associated with an increased risk of benign and malignant tumor formation predominantly on the skin, bone, and peripheral nervous system. It has been reported that out of all the NF1 cases, more than 95% cases develop the disease due to heterozygous loss-of-function variants in Neurofibromin (NF1) gene. However, identification of NF1 causative variants by presently recommended method of gene-targeted Sanger sequencing is challenging and cost-intensive due to the large size of the NF1gene with 60 exons spanning about 350 kb. Further, conducting the genetic studies is difficult in low resource regions and among families with the limited financial capabilities, restricting them from availing diagnostic as well as proper disease management measures. Here, we studied a three-generation family from Jammu and Kashmir state in India, with multiple affected family members showing clinical indications of NF1. We combinedly used two applications, Whole Exome Sequencing (WES) and Sanger sequencing, for this study and discovered a nonsense variant NM_000267.3:c.2041C>T (NP_000258.1:p.Arg681Ter*) in exon 18 of NF1 gene in a cost effective manner. In silico analyses further substantiated the pathogenicity of this novel variant. The study also emphasized on the role of Next Generation Sequencing (NGS) as a cost-effective method for the discovery of pathogenic variants in disorders with known phenotypes found in large sized candidate genes. The current study is the first study based on the genetic characterization of NF1 from Jammu and Kashmir–India, highlighting the importance of the described methodology adopted for the identification and understanding of the disease in low resource region. The early diagnosis of genetic disorders would open the door to appropriate genetic counseling, reducing the disease burden in the affected families and the general population at large. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatoid Arthritis (RA) is a systemic, chronic, inflammatory, and autoimmune disease which is characterised by the progressive ruination of joint structures. The Human Leukocyte Antigens (HLA) genes: HLA-DRB1 and HLA-DQB1, belonging to HLA family, presented on human chromosome six, are involved in the immune system. Various studies involving Genome-wide Association Studies (GWAS), meta-analysis, and replication studies have shown the association of HLA-DRB1 variant rs13192471 and HLA-DQB1 variant rs6457617 with RA susceptibility in different population groups. Aim: To perform a replication case-control based association study of variants rs13192471 and rs6457617, in order to determine their association with RA, in an independent cohort from the population of North-western India. Materials and Methods: The Case-control study conducted at Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India, duration of the study was, from May 2019 to June 2022. In this study, Deoxyribonucleic Acid (DNA) was isolated from 188 RA cases and 310 healthy controls, followed by qualitative and quantitative analyses. The genotyping was performed on a Real Time-polymerase Chain Reaction (RT-PCR) using TaqMan Allele Discrimination Assay. Statistical power of the study was estimated using PS: Power and sample size calculator version 3.1. Results: The statistical analysis of the genotyping data showed a significant association (p=0.005) of variant rs13192471 with RA susceptibility, whereas the variant rs6457617 did not show an association (p=0.275) with RA in the studied population cohort. Conclusion: The present study successfully replicated the association of HLA-DRB1 variant rs13192471 in the population group of North-western India. It is pertinent to screen these variants for RA susceptibility in other population groups of India before their use as potential genetic biomarkers in the Indian population. [ABSTRACT FROM AUTHOR]

Gastric Carcinoma (GC) is one of the most common malignancies, which accounts for 6.8% of total cancer population worldwide. In India, the northeastern region has the highest gastric cancer incidence, and the Kashmir Valley has a very high incidence of gastric cancer as compared to other parts of Northern India. It exceeds 40% of total cancers with an incidence rate of 3-6-fold higher than other metro cities of India. Gastric cancer is a heterogeneous disease where most of the cases are sporadic, and <15% are due to obvious familial clustering. The heterogeneous nature of the disease can be associated with differences in genetic makeup of an individual. A better understanding of genetic predisposition toward GC will be helpful in promoting personalized medicine. The aim of this review is to analyze the development and progression of GC and to explore the genetic perspectives of the disease with special emphasis on Jammu and Kashmir, India. [ABSTRACT FROM AUTHOR]

The metabolic syndrome is a cluster of heritable and related traits which has been associated with a range of pathophysiological factors including dyslipidaemia, abdominal obesity, increased fasting plasma glucose (FPG) and hypertension. The documented genetic basis of the metabolic syndrome include several chromosomal positions, numerous candidate gene-associated polymorphisms, different genetic variants, which are linked to the syndrome either as a trait or entities mainly linked to metabolic process. Additionally, the latest findings related to the contribution of epigenetic mechanisms, microRNAs, sporadic variants, non-coding RNAs, and assessing the role of genes in molecular systems has enhanced our understanding of the syndrome. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic etiology. Nonetheless, a common shared genetic cause has not been established to clarify the coexistence of their components and further investigation is required. While mostly neglected and rarely known, hereditary predisposition needs to be studied, including with the current defective phenotypic condition descriptions. Metabolic syndrome is a multi-faceted characteristic with abundant properties and the condition can arise from interactions between environmental variables such as physical inactivity, caloric obesity and genetic susceptibility. Although there is support for genetic determinants from family and twin research, there is still no recognised genomic DNA marker for genetic association and linkages with quite a long way off potential for clinical application. In the present review efforts have been made to through light on the various genetic determinants with large effects that underlie with the association of these traits to this syndrome. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge towards understanding the factors underlying the association of these traits. [ABSTRACT FROM AUTHOR]

Background: Leucine‑rich repeat and fibronectin type 2 gene (LRFN2) variant rs2494938 has recently been found associated with esophageal cancer in a genome‑wide association study in an Asian population. However, this association has not been replicated in any Indian population despite high incidence of the disease. Materials and Methods: In the present case–control study, 166 cases and 459 controls were included. Taqman assay technique using real‑time PCR was employed to investigate the association of the variant with esophageal cancer in the population of Jammu and Kashmir (J&K). The Hardy‑Weinberg equilibrium for rs2494938 was assessed using the Chi‑square test. The allele‑ and genotype‑specific risk was estimated by odds ratio (OR) with 95% confidence interval (CI). Results: Variant rs2494938 was observed to be significantly associated with esophageal cancer with an allelic OR of 1.59 (1.23–2.04 at 95% CI, P = 0.0003). Conclusion: The study highlights LRFN2 as a candidate gene for esophageal cancer susceptibility in the population of J&K and calls for a detailed study with a large sample size and involving more ethnic groups of India. [ABSTRACT FROM AUTHOR]

Background: Leucine-rich repeat and fibronectin type 2 gene (LRFN2) variant rs2494938 has recently been found associated with esophageal cancer in a genome-wide association study in an Asian population. However, this association has not been replicated in any Indian population despite high incidence of the disease.Materials and Methods: In the present case-control study, 166 cases and 459 controls were included. Taqman assay technique using real-time PCR was employed to investigate the association of the variant with esophageal cancer in the population of Jammu and Kashmir (J&K). The Hardy-Weinberg equilibrium for rs2494938 was assessed using the Chi-square test. The allele- and genotype-specific risk was estimated by odds ratio (OR) with 95% confidence interval (CI).Results: Variant rs2494938 was observed to be significantly associated with esophageal cancer with an allelic OR of 1.59 (1.23-2.04 at 95% CI, P = 0.0003).Conclusion: The study highlights LRFN2 as a candidate gene for esophageal cancer susceptibility in the population of J&K and calls for a detailed study with a large sample size and involving more ethnic groups of India. [ABSTRACT FROM AUTHOR]

Aim: Uncoupling protein 3 (UCP3) has been identified as a type 2 diabetes (T2D) candidate gene and variant rs1800849 is of potential interest as it is present in the regulatory region of UCP3. The aim of the present candidate gene case-control association study was to evaluate the association of variant rs1800849 of UCP3 with T2D in Mizo population from Northeast India. Methodology: The variation was genotyped using TaqMan allele discrimination assay in 767 individuals (425 cases and 342 healthy controls). Results: The variant rs1800849 of UCP3 was not found to be significantly associated with T2D (p-value = 0.733) in studied population group. Conclusion: Thus, it is concluded that the present study could not replicate the association of variant rs1800849 with genetic susceptibility to T2D in the Mizo population group. This absence of association highlights the genetic heterogeneity prevalent in Indian population groups and warrants screening of other T2D candidate genes in Mizo population group. [ABSTRACT FROM AUTHOR]

Rare diseases (RDs) are the clinical conditions affecting a few percentage of individuals in a general population compared to other diseases. Limited clinical information and a lack of reliable epidemiological data make their timely diagnosis and therapeutic management difficult. Emerging Next-Generation DNA Sequencing technologies have enhanced our horizons on patho-physiological understanding of many of the RDs and ushered us into an era of diagnostic and therapeutic research related to this ignored health challenge. Unfortunately, relevant research is meager in developing countries which lack a reliable estimate of the exact burden of most of the RDs. India is to be considered as the "Pandora's Box of genetic disorders." Owing to its huge population heterogeneity and high inbreeding or endogamy rates, a higher burden of rare recessive genetic diseases is expected and supported by the literature findings that endogamy is highly detrimental to health as it enhances the degree of homozygosity of recessive alleles in the general population. The population of a low resource region Jammu and Kashmir (J&K) – India, is highly inbred. Some of its population groups variably practice consanguinity. In context with the region's typical geographical topography, highly inbred population structure and unique but heterogeneous gene pool, a huge burden of known and uncharacterized genetic disorders is expected. Unfortunately, many suspected cases of genetic disorders remain undiagnosed or misdiagnosed due to lack of appropriate clinical as well as diagnostic resources in the region, causing patients to face a huge psycho-socio-economic crisis and many a time suffer life-long with their ailment. In this review, the major challenges associated with RDs are highlighted in general and an account on the methods that can be adopted for conducting fruitful molecular genetic studies in genetically vulnerable and low resource regions is also provided, with an example of a region like J&K – India. [ABSTRACT FROM AUTHOR]

Telomere length attrition has been implicated in various complex disorders including Type 2 Diabetes (T2D). However, very few candidate gene association studies have been carried out worldwide targeting telomere maintenance genes. In the present study, variants in various critical telomere maintenance pathway genes for T2D susceptibility in Northwest Indian population were explored. With case-control candidate gene association study design, twelve variants from seven telomere maintenance genes were evaluated. Amongst these five variants, rs9419958 (OBFC1), rs4783704 (TERF2), rs16847897 (TERC/LRRC31), rs10936599 (TERC/MYNN), and rs74019828 (CSNK2A2) showed significant association with T2D (at p-value ≤ 0.003, threshold set after Bonferroni correction) in the studied population. In silico analyses of these variants indicated interesting functional roles that warrant experimental validations. Findings showed that variants in telomere maintenance genes are associated with pathogenesis of T2D in Northwest Indian population. We anticipate further, such candidate gene association studies in other Indian populations and worldwide would contribute in understanding the missing heritability of T2D. [ABSTRACT FROM AUTHOR]

Aim: Microtubule actin cross-linking factor 1 (MACF1) has been identified as a type 2 diabetes (T2D) candidate gene, and variant rs2296172 of the gene was found associated with T2D in multiple populations. However, it has never been explored in Mizo population. The aim of the present study was to replicate the association of variant rs2296172 of MACF1 gene with T2D in Mizo population of Northeast India. Methodology: The variation was genotyped using TaqMan allele discrimination assay in 755 individuals (425 cases and 330 healthy controls), belonging to the Mizo population. Results: The variant rs2296172 MACF1 was found to be significantly associated with T2D (p value = 0.001) in Mizo population group with an observed odds ratio of 1.8 [1.3–2.8] at 95% CI after correction with age, gender and BMI. Conclusion: This study is the first replication report from Northeast India, showing variant rs2296172 of MACF1 gene associated with T2D in Mizo population. This independent study highlights MACF1 as a candidate gene for T2D in Asian Indian populations, suggesting it is critical to evaluate the variant rs2296172 in other distinct endogamous Indian population cohorts. [ABSTRACT FROM AUTHOR]

Background: Narrow genetic base, complex allo-tetraploid genome and presence of repetitive elements have led the discovery of single nucleotide polymorphisms (SNPs) in Brassica juncea (AABB; 2n = 4x = 36) at a slower pace. Double digest RAD (ddRAD) - a genome complexity reduction technique followed by NGS was used to generate a total of 23 million paired-end reads from three genotypes each of Indian (Pusa Tarak, RSPR-01 and Urvashi) and Exotic (Donskaja IV, Zem 1 and EC287711) genepools. Results: Sequence data analysis led to the identification of 10,399 SNPs in six genotypes at a read depth of 10x coverage among the genotypes of two genepools. A total of 44 hyper-variable regions (nucleotide variation hotspots) were also found in the genome, of which 93% were found to be a part of coding genes/regions. The functionality of the identified SNPs was estimated by genotyping a subset of SNPs on MassARRAY® platform among a diverse set of B. juncea genotypes. SNP genotyping-based genetic diversity and population studies placed the genotypes into two distinct clusters based mostly on the place of origin. The genotypes were also characterized for six morphological traits, analysis of which revealed a significant difference in the mean values between Indian and Exotic genepools for six traits. The association analysis for six traits identified a total of 45 significant marker-trait associations on 11 chromosomes of A- and B- group of progenitor genomes. Conclusions: Despite narrow diversity, the ddRAD sequencing was able to identify large number of nucleotide polymorphisms between the two genepools. Association analysis led to the identification of common SNPs/genomic regions associated between flowering and maturity traits, thereby underscoring the possible role of common chromosomal regions-harboring genes controlling flowering and maturity in Brassica juncea. [ABSTRACT FROM AUTHOR]

Microtubule actin cross-linking factor 1 (MACF1) gene variant rs2296172 has recently been associated with type 2 diabetes (T2D). However, this variant has never been evaluated as such in Indian populations. In the present replication study, we genotyped variant rs2296172 by Taqman allele discrimination assay in 432 individuals belonging to the Bania caste group from Punjab, India. The single-nucleotide polymorphism (SNP) was evaluated for association with T2D, in a population based candidate gene case-control association study design, by estimating odds ratio with 95% confidence interval. The SNP rs2296172 of MACF1 was found to be significantly associated with T2D (p = 0.02) and odds ratio (OR) = 1.59 (1.06-2.38) at 95% CI. We further emphasize that the Indian population as such is a conglomeration of various endogamous population groups. It is critical that such replication studies be carried out in various populations to find association of variants to T2D susceptibility and understand genetic heterogeneity. However, it is important to avoid pooling of samples to address the concern of population stratification. [ABSTRACT FROM AUTHOR]

Background Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). Methods Here, we report the first ICSG study, a metaanalysis of the LBX1 locus in six Asian and three non- Asian cohorts. Results We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10-43 for rs11190870, and P=2.94×10-48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ~25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. Conclusions Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups. [ABSTRACT FROM AUTHOR]

We sought to identify risk factors for type 2 diabetes (T2D) in Jammu and Kashmir populations, India. A total of 424 diabetic and 226 non-diabetic subjects from Jammu, and 161 diabetic and 100 non-diabetic subjects from Kashmir were screened for various parameters including fasting blood glucose level, 2 hour glucose level, urea, creatinine, triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein (VLDL-C), uric acid, systolic and diastolic blood pressure level. We found that subjects aged 40-49 years had the highest rate of diabetes, with family income playing not much of a role. Kashmiri migrants or populations with rapid cultural, environmental, social or lifestyle change along with reduced physical activity, obesity and unhealthy lifestyle (smoking and alcohol consumption) were found to have higher rates of diabetes. High blood glucose, triglycerides and low HDL-C levels were found to be contributing to disease outcome. High blood pressure also contributed to a higher risk of developing T2D. Our study supports earlier reports confirming the contribution of comfortable life style, Western dietary habits and rapid life style change along with many other factors to the prevalence of diabetes. This may contribute to the epidemic proportion of diabetes in Jammu and Kashmir. Early diagnosis and routine screening for undiagnosed diabetes in obese subjects and subjects with parental diabetes history is expected to decrease the burden of chronic diabetic complications worldwide. [ABSTRACT FROM AUTHOR]

Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls. To identify additional AIS-associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 × 10−10; odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein-coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 × 10−14; OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a syndrome of multiple metabolic disorders and is genetically heterogeneous. India comprises one of the largest global populations with highest number of reported type 2 diabetes cases. However, limited information about T2D associated loci is available for Indian populations. It is, therefore, pertinent to evaluate the previously associated candidates as well as identify novel genetic variations in Indian populations to understand the extent of genetic heterogeneity. We chose to do a cost effective high-throughput mass-array genotyping and studied the candidate gene variations associated with T2D in literature. In this case-control candidate genes association study, 91 SNPs from 55 candidate genes have been analyzed in three geographically independent population groups from India. We report the genetic variants in five candidate genes: TCF7L2, HHEX, ENPP1, IDE and FTO, are significantly associated (after Bonferroni correction, p<5.5E−04) with T2D susceptibility in combined population. Interestingly, SNP rs7903146 of the TCF7L2 gene passed the genome wide significance threshold (combined P value = 2.05E−08) in the studied populations. We also observed the association of rs7903146 with blood glucose (fasting and postprandial) levels, supporting the role of TCF7L2 gene in blood glucose homeostasis. Further, we noted that the moderate risk provided by the independently associated loci in combined population with Odds Ratio (OR)<1.38 increased to OR = 2.44, (95%CI = 1.67–3.59) when the risk providing genotypes of TCF7L2, HHEX, ENPP1 and FTO genes were combined, suggesting the importance of gene-gene interactions evaluation in complex disorders like T2D. [ABSTRACT FROM AUTHOR]

Background: Adolescent idiopathic scoliosis (AIS) is one of the most common spinal deformities found in adolescent populations. Recently, a genome-wide association study (GWAS) in a Japanese population indicated that three single nucleotide polymorphisms (SNPs), rs11190870, rs625039 and rs11598564, all located near the LBX1 gene, may be associated with AIS susceptibility [1]. This study suggests a novel AIS predisposition candidate gene and supports the hypothesis that somatosensory functional disorders could contribute to the pathogenesis of AIS. These findings warrant replication in other populations. Methodology/Principal Findings:First, we conducted a case-control study consisting of 953 Chinese Han individuals from southern China (513 patients and 440 healthy controls), and the three SNPs were all found to be associated with AIS predisposition. The ORs were observed as 1.49 (95% CI 1.23-1.80, P = 5.09E-5), 1.70 (95% CI 1.42-2.04, P = 1.17E-8) and 1.52 (95% CI 1.27-1.83, P = 5.54E-6) for rs625039, rs11190870 and rs11598564, respectively. Second, a case-only study including a subgroup of AIS patients (N = 234) was performed to determine the effects of these variants on the severity of the condition. However, we did not find any association between these variants and the severity of curvature. Conclusion:This study shows that the genetic variants near the LBX1 gene are associated with AIS susceptibility in Chinese Han population. It successfully replicates the results of the GWAS, which was performed in a Japanese population. [ABSTRACT FROM AUTHOR]

Our previous studies have implicated genes mainly involved in the activity of pancreatic b cells in type 2 diabetes (T2D) susceptibility in the North Indian population. Recent literature on the role of SIRT1 as a potential master switch modulating insulin secretion and regulating gene expression in pancreatic b cells has warranted an evaluation of SIRT1 promoter region polymorphisms in the North Indian population, which is the main focus of the present study. 1542 samples (692 T2D patients and 850 controls) were sequenced for the 1.46 kb region upstream the translation start site of the SIRT1 gene. We performed a functional characterization of the SIRT1 promoter region polymorphisms using luciferase assay and observed a single-nucleotide polymorphism (SNP), rs12778366, in association with SIRT1 expression. We propose that TT, the highexpressing genotype of SNP rs12778366 in the SIRT1 promoter region and present in .80% of the North Indian population, was favored under conditions of feast-famine cycles in evolution, which has turned out to be a cause of concern in the present sedentary lifestyle under ad libitum conditions. Case-control association analysis did not implicate rs12778366 in T2DM per se in the studied population. However, our earlier reported risk genotype combinations of mt-ND3, PGC1a, and UCP2-866, when compared with the protective genotype combinations, in the background of the high-expressing TT genotype of SIRT1 SNP rs12778366, showed a very high additive risk [corrected odd ratio (OR) = 8.91; p = 6.5 x 10-11]. The risk level was considerably low in the genotype backgrounds of TX (OR = 6.68; p = 2.71 x 10-12) and CX (OR = 3.74; p = 4.0 x 10-3). In addition, we screened other reported T2D-associated polymorphisms: PIK3R1 rs3730089, IRS1 rs1801278, and PPP1R3 rs1799999, which did not show any significant association in North Indian population. The present paper emphasizes the importance of gene interactions in the biological pathways of T2D, a complex lifestyle disease. [ABSTRACT FROM AUTHOR]

Leptin has been suggested to play a role in the etiology of Adolescent Idiopathic Scoliosis (AIS), however, the leptin levels in AIS girls are still a discrepancy, and no in vitro study of leptin in AIS is reported. We took a series of case-control studies, trying to understand whether Leptin gene polymorphisms are involved in the etiology of the AIS or the change in leptin level is a secondary event, to assess the level of leptin receptor, and to evaluate the differences of response to leptin between AIS cases and controls. We screened all exons of Leptin gene in 45 cases and 45 controls and selected six tag SNPs to cover all the observed variations. Association analysis in 446 AIS patients and 550 healthy controls showed no association between the polymorphisms of Leptin gene and susceptibility/severity to AIS. Moreover, adipogenesis assay of bone mesenchymal stem cells (MSCs) suggested that the adipogenic ability of MSCs from AIS girls was lower than controls. After adjusting the differentiation rate, expressions of leptin and leptin receptor were similar between two groups. Meanwhile, osteogenesis assay of MSC showed the leptin level was similar after adjusting the differentiation rate, but the leptin receptor level was decreased in induced AIS osteoblasts. Immunocytochemistry and western blot analysis showed less leptin receptors expressed in AIS group. Furthermore, factorial designed studies with adipogenesis and osteogenesis revealed that the MSCs from patients have no response to leptin treatment. Our results suggested that Leptin gene variations are not associated with AIS and low serum leptin probably is a secondary outcome which may be related to the low capability of adipogenesis in AIS. The decreased leptin receptor levels may lead to the hyposensitivity to leptin. These findings implied that abnormal peripheral leptin signaling plays an important role in the pathological mechanism of AIS. [ABSTRACT FROM AUTHOR]

Many major rival models of the origin of the Hindu caste system co-exist despite extensive studies, each with associated genetic evidences. One of the major factors that has still kept the origin of the Indian caste system obscure is the unresolved question of the origin of Y-haplogroup R1a1*, at times associated with a male-mediated major genetic influx from Central Asia or Eurasia, which has contributed to the higher castes in India. Y-haplogroup R1a1* has a widespread distribution and high frequency across Eurasia, Central Asia and the Indian subcontinent, with scanty reports of its ancestral (R*, R1* and R1a*) and derived lineages (R1a1a, R1a1b and R1a1c). To resolve these issues, we screened 621 Y-chromosomes (of Brahmins occupying the upper-most caste position and schedule castes/tribals occupying the lower-most positions) with 55 Y-chromosomal binary markers and seven Y-microsatellite markers and compiled an extensive dataset of 2809 Y-chromosomes (681 Brahmins, and 2128 tribals and schedule castes) for conclusions. A peculiar observation of the highest frequency (up to 72.22%) of Y-haplogroup R1a1* in Brahmins hinted at its presence as a founder lineage for this caste group. Further, observation of R1a1* in different tribal population groups, existence of Y-haplogroup R1a* in ancestors and extended phylogenetic analyses of the pooled dataset of 530 Indians, 224 Pakistanis and 276 Central Asians and Eurasians bearing the R1a1* haplogroup supported the autochthonous origin of R1a1 lineage in India and a tribal link to Indian Brahmins. However, it is important to discover novel Y-chromosomal binary marker(s) for a higher resolution of R1a1* and confirm the present conclusions.Journal of Human Genetics (2009) 54, 47–55; doi:10.1038/jhg.2008.2; published online 9 January 2009 [ABSTRACT FROM AUTHOR]

The recent observations that Peroxisome proliferator activated receptor gamma coactivator 1 alpha ( PGC1A) is responsible for the induction of reactive oxygen species (ROS) detoxifying agents and that ROS triggers insulin resistance, support the role that this gene could play in the onset of Type 2 diabetes mellitus (T2DM). Two PGC1A variants Thr394Thr (rs2970847) and Gly482Ser (rs8192673) were genotyped in 822 subjects (351 T2DM cases and 471 controls) from two North Indian populations, represented as Group 1 (Kashmir population) and Group 2 (Punjab and Jammu population). Both Groups 1 and 2 showed a significant association of Thr394Thr variant with T2DM after applying Bonferroni corrections ( P = 0.001 and 0.012, respectively). Logistic regression analysis for Thr394Thr susceptible genotypes together (rs2970847 G/A and A/A) conferred a 1.89-(95%CI 1.25–2.85) fold higher risk for T2DM in Group 1 and 1.81-(95%CI 1.19–2.78) fold risk in Group 2. The susceptible, Ser482 (rs8192673 G/A and A/A) genotypes, gave a 2.04 (95%CI 1.47–3.03) fold higher risk for T2DM in Group 1. Mitochondrial genotype backgrounds observed in association with T2DM (Bhat et al. ), when studied in combination with PGC1A variants, showed an increased prevalence in controls with mt10398G and 16189T along with G/G genotype background at the two polymorphic loci of PGC1A. These observations suggest that the two genotype backgrounds together could provide protection against T2DM. [ABSTRACT FROM AUTHOR]

Background: Y-chromosomal haplogroup (Y-HG) Q is suggested to originate in Asia and represent recent founder paternal Native American radiation into the Americas. This group is delineated into Q1, Q2 and Q3 subgroups defined by biallelic markers M120, M25/M143 and M3, respectively. Recently, a novel subgroup Q4 has been identified which is defined by bi-allelic marker M346, representing HG Q (0.41%, 3/728) in Indian population. With scanty details of HG Q in Asia, especially India, it was pertinent to explore the status of the Y-HG Q in Indian population to gather an insight to determine the extent of diversity within this region. Results: We observed 15/630 (2.38%) Y-HG Q individuals in India with an ancestral state at M120, M25, M3 and M346 markers, indicating an absence of already known Q1, Q2, Q3 and Q4 subhaplogroups. Interestingly, we further observed a novel 4 bp deletion/insertion polymorphism (ss4 bp, rs41352448) at 72,314 position of human arylsulfatase D pseudogene, defining a novel sublineage Q5 (in 5/15 individuals, i.e., 33.3 % of the observed Y-HG Q) with distributions independent of the social, cultural, linguistic and geographical affiliations in India. Conclusion: The study adds another sublineage Q5 in the already existing arrangement of Y-HG Q in literature. It was quite interesting to observe an ancestral state Q* and a novel sub-branch Q5, not reported elsewhere, in Indian subcontinent, though in low frequency. A novel subgroup Q4 was identified recently which is also restricted to Indian subcontinent. The most plausible explanation for these observations could be an ancestral migration of individuals bearing ancestral lineage Q* to Indian subcontinent followed by an autochthonous differentiation to Q4 and Q5 sublineages later on. However, other explanations of, either the presence of both the sub haplogroups (Q4 and Q5) in ancestral migrants or recent migrations from central Asia, cannot be ruled out till the distribution and diversity of these subgroups is explored extensively in Central Asia and other regions. [ABSTRACT FROM AUTHOR]

The role of mitochondria in causing diseases is becoming evident as more and more studies are focusing on this organelle of the cell. This is largely attributed to its reactive oxygen species (ROS) production property. In the context of diabetes, ROS is suggested to trigger different forms of insulin resistance involving different mechanisms. The suggestive role of a mtDNA variant G10398A in increasing ROS production and the impaired response to oxidative stress due to T16189C variant is worth addressing as genetic susceptibility factors in type 2 diabetes mellitus (T2DM). A case control study on 312 T2DM cases and ethnically matched 466 controls involving two North Indian populations, referred as cohort 1 and cohort 2 (in a replicative study), was undertaken to test such a genetic association. A statistically significant association was observed for 10398A allele in both the cohorts [cohort1 (OR = 2.67 95% CI 1.77–4.00); cohort2 (OR = 1.76 95%CI 1.12–2.77)]. The analysis of G10398A/T16189C haplotypic combinations revealed that 10398A/16189C haplotype provides a risk in both the cohorts. To sum up the study suggests that 10398A and 16189C alleles provide susceptiblity to T2DM independently as well as together. [ABSTRACT FROM AUTHOR]

The minor haplotype −3575A/-2849G/-2763C in IL-10 promoter has been defined as a marker of disease resistance to leprosy and its severity in Brazilian population. Our investigation of six single-nucleotide polymorphisms (SNPs) in IL-10 promoter in 282 Indian leprosy patients and 266 healthy controls by direct PCR sequencing, however, showed that the extended haplotype: −3575T/-2849G/-2763C/-1082A/-819C/-592C was associated with resistance to leprosy per se and to the development of severe form of leprosy, using either a binomial (controls vs cases, P=0.01, OR=0.58, CI=0.37–0.89) or ordinal (controls vs paucibacillary vs multibacillary, P=0.004) model. Whereas, IL-10 haplotype −3575T/-2849G/-2763C/-1082A/-819T/-592A was associated with the risk of development of severe form of leprosy ( P=0.0002) in contrast to the minor risk haplotype −3575T/-2849A/-2763C in the Brazilian population. The role of IL-10 promoter SNPs in Brazilian and Indian population strongly suggests the involvement of IL-10 locus in the outcome of leprosy. [ABSTRACT FROM AUTHOR]

We have analysed the hypervariable regions (HVR I and II) of human mitochondrial DNA (mtDNA) in individuals from Uttar Pradesh (UP), Bihar (BI) and Punjab (PUNJ), belonging to the Indo-European linguistic group, and from South India (SI), that have their linguistic roots in Dravidian language. Our analysis revealed the presence of known and novel mutations in both hypervariable regions in the studied population groups. Median joining network analyses based on mtDNA showed extensive overlap in mtDNA lineages despite the extensive cultural and linguistic diversity. MDS plot analysis based on Fst distances suggested increased maternal genetic proximity for the studied population groups compared with other world populations. Mismatch distribution curves, respective neighbour joining trees and other statistical analyses showed that there were significant expansions. The study revealed an ancient common ancestry for the studied population groups, most probably through common founder female lineage(s), and also indicated that human migrations occurred (maybe across and within the Indian subcontinent) even after the initial phase of female migration to India. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Four binary polymorphisms and four multiallelic short tandem repeat (STR) loci from the nonrecombining region of the human Y-chromosome were typed in different Indian population groups from Uttar Pradeh (UP), Bihar (BI), Punjab (PUNJ), and Bengal (WB) speaking the Indo-Aryan dialects and from South India (SI) with the root in the Dravidian language. We identified four major haplogroups [(P) 1+, (C and F) 2+, (R1a) 3, (K) 26+] and 114 combinations of Y-STR haplotypes. Analyses of the haplogroups indicated no single origin from any lineage but a result of a conglomeration of different lineages from time to time. The phylogenetic analyses indicate a high degree of population admixture and a greater genetic proximity for the studied population groups when compared with other world populations. [ABSTRACT FROM AUTHOR]

A correction to the article "PGC-1α Thr394Thr and Gly482Ser Variants are Significantly Associated With T2DM in Two North Indian Populations: A Replicate Case-Control Study" is presented.