Department Of Human Genetics And Molecular Medicine
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Item Variants in KCNQ1 increase type II diabetes susceptibility in South Asians: A study of 3,310 subjects from India and the US(2011) Been, L.F.; Ralhan, S.; Wander, G.S.; Mehra, N.K.; Singh, J.; Mulvihill, J.J.; Aston, C.E.; Sanghera, D.K.Background: Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS). More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US.Methods: We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US.Results: Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362) with T2D showing an allelic odds ratio (OR) of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036) and combined cohorts (meta-analysis OR 1.14; p = 0.018). Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 ? 10-4in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).Conclusions: Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through ? cell function. ? 2011 Been et al; licensee BioMed Central Ltd.Item Shared and unique common genetic determinants between pediatric and adult celiac disease(BioMed Central Ltd., 2016) Senapati, S.; Sood, A.; Midha, V.; Sood, N.; Sharma, S.; Kumar, L.; Thelma, B.K.Background: Based on age of presentation, celiac disease (CD) is categorised as pediatric CD and adult CD. It however remains unclear if these are genetically and/or phenotypically distinct disorders or just different spectrum of the same disease. We therefore explored the common genetic components underlying pediatric and adult CD in a well characterized north Indian cohort. Methods: A retrospective analysis of children (n = 531) and adult (n = 871) patients with CD between January 2001 and December 2010 was done. The database included basic demographic characteristics, clinical presentations, associated diseases and complications, if any. The genotype dataset was acquired for children (n = 217) and adult CD patients (n = 340) and controls (n = 736) using Immunochip. Association analysis was performed using logistic regression model to identify susceptibility genetic variants. Results: The predominant form of CD was classical CD in both pediatric and adult CD groups. There was remarkable similarity between pediatric and adult CD except for quantitative differences between the two groups such as female preponderance, non-classical presentation, co-occurrence of other autoimmune diseases being more common amongst adult CD. Notably, same HLA-DQ2 and -DQ8 haplotypes were established as the major risk factors in both types of CD. In addition, a few suggestively associated (p < 5 ? 10-4) non-HLA markers were identified of which only ANK3 (rs4948256-A; rs10994257-T) was found to be shared and explain risk for ?45 % of CD patients with HLA allele. Discussion: Overall phenotypic similarity between pediatric and adult CD groups can be explained by contribution of same HLA risk alleles. Different non-HLA genes/loci with minor risk seem to play crucial role in disease onset and extra intestinal manifestation of CD. None of the non-HLA risk variants reached genome-wide significance, however most of them were shown to have functional implication to disease pathogenesis. Functional relevance of our findings needs to be investigated to address clinical heterogeneity of CD. Conclusions: This present study is the first comparative study based on common genetic markers to suggest that CD in pediatric age group and in adults are the spectrum of the same disease with novel and shared genetic risk determinants. Follow-up fine mapping studies with larger study cohorts are warranted for further genetic investigation. ? 2016 The Author(s).Item Ring chromosome 22: A review of the literature and first report from India(2012) Mahajan, S.; Kaur, A.; Singh, Jai RoopRing chromosome 22 [r(22)], a rare cytogenetic finding, has been described in nearly 70 cases to date. Cytogenetic investigations were carried out on a 5-year-old male child with microcephaly and intellectual disability. Cytogenetic investigations revealed his karyotype to be 46, XY, r(22). To the best of our knowledge, this is the first report of an r(22) anomaly from India.Item Role of TLR4 (C1196T) and CD14 (C-260T) Polymorphisms in Development of Ischemic Stroke, Its Subtypes and Hemorrhagic Stroke(Springer New York LLC, 2017) Das, Satrupa; Kaul, & Subhash; Jyothy, Akka; Munshi, AnjanaIn the present study, we evaluated the association of TLR4 and CD14 polymorphisms, i.e. C1196T and C-260T, respectively, with ischemic stroke (n?=?700), its subtypes and hemorrhagic stroke (n?=?300) in a South Indian population from Telangana. The genotypes were determined using PCR?RFLP, and the strength of association between genotypes and stroke was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. The results revealed a lack of association for TLR4 variant with ischemic stroke and hemorrhagic stroke, although a significant association was observed with the subtypes extracranial large artery (p?=?0.008), other determined aetiology (p?=?0.03) and undetermined aetiology (p?=?0.01). Investigations on the variant of CD14 gene revealed negative association among ischemic stroke patients; however, a significant association was observed for hemorrhagic stroke following dominant and recessive genotypic model (p?=?0.05, p?=?0.02). Among ischemic stroke subtype, a significant association was observed with intracranial large artery, extracranial large artery, other determined aetiology and undetermined aetiology form of stroke (p?Item Regulation of GAD65 expression by SMAR1 and p53 upon Streptozotocin treatment(2012) Singh, Sandeep; Raina, Varsheish; Chavali, Pavithra Lakshminarsimhan; Dubash, Taronish; Kadreppa, Sreenath; Parab, Pradeep; Chattopadhyay, SamitBackground: GAD65 (Glutamic acid decarboxylase 65 KDa isoform) is one of the most important auto-antigens involved in Type 1 diabetes induction. Although it serves as one of the first injury markers of ?-islets, the mechanisms governing GAD65 expression remain poorly understood. Since the regulation of GAD65 is crucial for the proper functioning of insulin secreting cells, we investigated the stress induced regulation of GAD65 transcription.Results: The present study shows that SMAR1 regulates GAD65 expression at the transcription level. Using a novel protein-DNA pull-down assay, we show that SMAR1 binding is very specific to GAD65 promoter but not to the other isoform, GAD67. We show that Streptozotocin (STZ) mediated DNA damage leads to upregulation of SMAR1 and p53 expression, resulting in elevated levels of GAD65, in both cell lines as well as mouse ?-islets. SMAR1 and p53 act synergistically to up-regulate GAD65 expression upon STZ treatment.Conclusion: We propose a novel mechanism of GAD65 regulation by synergistic activities of SMAR1 and p53. ? 2012 Singh et al.; licensee BioMed Central Ltd.Item Recent advances in HER2 positive breast cancer epigenetics: Susceptibility and therapeutic strategies(Elsevier Masson SAS, 2017) Singla, Heena; Ludhiadch, Abhilash; Kaur, Raman Preet; Chander, Harish; Kumar, Vinod; Munshi, AnjanaHER2 amplification/overexpression accounts for aggressive clinical features of HER2 positive breast cancer. Epigenetic changes including DNA methylation, histone modifications and ncRNAs/miRNAs are associated with regulation of DNA chromatin and specifically, gene transcription. Hence, these produce eminent effects upon proto-oncogenes, tumor-suppressors and key cancer-regulatory signaling pathways. Understanding of epigenomic regulation of HER2 overexpression and signaling may help uncover the unmatchable physiology of HER2 gene/protein. Moreover, this may also aid in resolving the major issue of resistance-development towards HER2 targeted agents (trastuzumab and lapatinib), since epigenetic alterations are important therapeutic markers and modulate the response towards HER2 targeted therapy. Therefore, in this review the information regarding various epigenetic markers implicated in HER2 positive breast cancer susceptibility and therapeutic-strategies has been compiled. ? 2017 Elsevier Masson SASItem Oxidative stress in the development of genetic generalised epilepsy: An observational study in southern Indian population(Journal of Clinical and Diagnostic Research, 2017) Prasad, D.K.V.; Satyanarayana, U.; Shaheen, U.; Surya Prabha, T.; Munshi, A.Introduction: Oxidative stress resulting from excessive generation of Reactive Oxygen Species (ROS) plays a significant role in neurodegeneration associated with seizures/epilepsy. Aim: To evaluate oxidative stress markers and antioxidant enzymes in Genetic Generalised Epilepsy (GGE) and to know the extent of oxidative stress induced by Anti-Epileptic Drugs (AEDs) with the time duration of treatment. Materials and Methods: In this case-control study, 310 GGE patients (male:female=203:107), who were on AED treatment (n=235) and 75 untreated patients (male:female=49:26) along with 310 age and sex matched healthy controls were recruited. Oxidative stress markers such as Nitric Oxide (NO), Malondialdehyde (MDA) and antioxidant enzyme activities namely Superoxide Dismutase (SOD), Glutathione Peroxidase (GPx) and Catalase (CAT) were measured spectrophotometrically. Results: Significantly higher levels of serum NO, MDA and low levels of plasma Total Antioxidant Capacity (TAC) were found in patients as compared to controls (p<0.001) whereas erythrocyte SOD, CAT and GPx activities were found to be significantly low in patients when compared to the control group (p<0.001). Statistically significant higher levels of NO, MDA and lower levels of SOD, CAT and TAC were observed in patients subgroup, who were on AEDs for more than >5 years compared to other groups (? 1 year and 1-? 5 years) (p=0.02, p=0.01, p=0.001, p=0.01 and p=0.05 respectively). Further, significant increase in the levels of NO, MDA and decreased activities of SOD, CAT were found in treated patients compared to untreated patients (p<0.05) denoting that additional oxidative stress induced by AEDs which results in seizure recurrence and drug intractability. Conclusion: Our study demonstrated that GGE patients have additional oxidative stress due to AEDs and decreased antioxidant enzyme activities causing an imbalance between oxidant and antioxidant status, which might contribute to the pathogenesis of GGE. ? 2017, Journal of Clinical and Diagnostic Research. All rights reserved.Item miR-30c and miR-181a synergistically modulate p53?p21 pathway in diabetes induced cardiac hypertrophy(Springer New York LLC, 2016) Raut, Satish K.; Singh, Gurinder B.; Rastogi, Bhawna; Saikia, Uma Nahar; Mittal, Anupam; Dogra, Nilambra; Singh, Sandeep; Prasad, Rishikesh; Khullar, Madhup53?p21 pathway mediates cardiomyocyte hypertrophy and apoptosis and is upregulated in diabetic cardiomyopathy (DbCM). We investigated role of microRNAs in regulating p53?p21 pathway in high glucose (HG)-induced cardiomyocyte hypertrophy and apoptosis. miR-30c and miR-181a were identified to target p53. Cardiac expression of microRNAs was measured in diabetic patients, diabetic rats, and in HG-treated cardiomyocytes. Effect of microRNAs over-expression and inhibition on HG-induced cardiomyocyte hypertrophy and apoptosis was examined. Myocardial expression of p53 and p21 genes was increased and expression of miR-30c and miR-181a was significantly decreased in diabetic patients, DbCM rats, and in HG-treated cardiomyocytes. Luciferase assay confirmed p53 as target of miR-30c and miR-181a. Over-expression of miR-30c or miR-181a decreased expression of p53, p21, ANP, cardiomyocyte cell size, and apoptosis in HG-treated cardiomyocytes. Concurrent over-expression of these microRNAs resulted in greater decrease in cardiomyocyte hypertrophy and apoptosis, suggesting a synergistic effect of these microRNAs. Our results suggest that dysregulation of miR-30c and miR-181a may be involved in upregulation of p53?p21 pathway in DbCM. ? 2016, Springer Science+Business Media New York.Item Interleukin 1ß (+3954, -511 and -31) polymorphism in chronic periodontitis patients from North India(Informa Healthcare, 2015) Amirisetty, Ramesh; Patel, Ritu Prabha; Das, Satrupa; Saraf, Jitendra; Jyothy, Akka; Munshi, AnjanaObjective. Several studies have implicated the role of interleukin-1 in various chronic diseases including periodontitis. The present study was carried out with an aim to evaluate the role of interleukin 1? polymorphisms, namely +3954C/T, -511C/T and -31T/C, in the development of chronic periodontitis. Materials and methods. Twenty-nine chronic periodontitis patients and 31 healthy controls of North Indian origin from Chhattisgarh were recruited for the study. The genotypes for the three variants were determined using the PCR-RFLP technique and the strength of association between genotypes and periodontitis was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. Results. Analysis for the +3954 allelic and genotypic frequencies of the polymorphism revealed a significant difference in the CT genotype between periodontitits patients and controls (p = 0.03). A significant difference was also observed in the allelic frequencies between the two groups (p = 0.02). For the -511 site, TT genotype revealed a significant association with the disease (p = 0.01). A significant association was also found following the co-dominant model (p = 0.007). However, the -31 polymorphism revealed no significant difference between patients and controls. Conclusions. In conclusion, the present study suggests a strong association of the TT genotype of -511 and CT genotype of +3954 variant of interleukin 1? with chronic periodontitis. However, the -31 variant did not show a significant association with the disease. ? Informa Healthcare.Item Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India(American Diabetes Association Inc., 2013) Saxena, R.; Saleheen, D.; Been, L.F.; Garavito, M.L.; Braun, T.; Bjonnes, A.; Young, R.; Ho, W.K.; Rasheed, A.; Frossard, P.; Sim, X.; Hassanali, N.; Radha, V.; Chidambaram, M.; Liju, S.; Rees, S.D.; Ng, D.P.-K.; Wong, T.-Y.; Yamauchi, T.; Hara, K.; Tanaka, Y.; Hirose, H.; McCarthy, M.I.; Morris, A.P.; Basit, A.; Barnett, A.H.; Katulanda, P.; Matthews, D.; Mohan, V.; Wander, G.S.; Singh, J.R.; Mehra, N.K.; Ralhan, S.; Kamboh, M.I.; Mulvihill, J.J.; Maegawa, H.; Tobe, K.; Maeda, S.; Cho, Y.S.; TaWe performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10-3) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10-4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 ? 10-8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10-3) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10-4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10-5 to < 10-7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis. ? 2013 by the American Diabetes Association.