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 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 PPARG and ADIPOQ gene polymorphisms increase type 2 diabetes mellitus risk in Asian Indian Sikhs: Pro12Ala still remains as the strongest predictor(2010) Sanghera, D.K.; Demirci, F.Y.; Been, L.; Ortega, L.; Ralhan, S.; Wander, G.S.; Mehra, N.K.; Singh, J.; Aston, C.E.; Mulvihill, J.J.; Kamboh, I.M.We have examined the association of 14 tagging single nucleotide polymorphisms (tagSNPs) in peroxisome proliferator activated receptor-? transcripts 1 and 2 (PPARG1 and 2) and 5 tagSNPs in adiponectin (ADIPOQ) genes for their effect on type 2 diabetes mellitus (T2D) risk in Asian Indian Sikhs. A total of 554 T2D cases and 527 normoglycemic controls were examined for association with T2D and other subphenotypes of T2D. With the exception of a strong association of PPARG2/Pro12Ala with T2D (odds ratio, 0.13; 95% confidence interval, 0.03-0.56; P = .0007), no other tagSNP in the PPARG locus revealed any significant association with T2D in this population. Similarly, none of the tagSNPs in the ADIPOQ gene was associated with T2D susceptibility in single-site analysis. However, haplotype analysis provided strong evidence of association of these loci with T2D. Three-site haplotype analysis in the PPARG locus using the 2 marginally associated SNPs (P/rs11715073 and P/rs3892175) in combination with Pro12 Ala (P/rs1801282) revealed a strong association of 1 "risk" (CGC) (P = .003, permutation P = .015) and 1 "protective" (CAC) (P = .001, permutation P = .005) haplotype associated with T2D. However, the major effect still appears to be driven by Pro12Ala, as the association of these haplotypes did not remain significant when analyzed conditional upon Pro12Ala (P = .262). In addition, 2-site haplotype analysis in the ADIPOQ locus using only 2 marginally associated SNPs (AD/rs182052 and AD/rs7649121) revealed a significant protective association of the GA haplotype with T2D (P = .009, permutation P = .026). Multiple linear regression analysis also revealed significant association of an ADIPOQ variant (AD/rs12495941) with total body weight (P = .010), waist (P = .024), and hip (P = .021), although these associations were not significant after adjusting for multiple testing. Our new findings strongly suggest that the genetic variation in PPARG and ADIPOQ loci could contribute to the risk for the development of T2D in Indian Sikhs. Identification of causal SNPs in these important biological and positional candidate genes would help determine the true physiologic significance of these loci in T2D and obesity. ? 2010 Elsevier Inc. All rights reserved.Item 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 Association of GABRA6 1519 T>C (rs3219151) and Synapsin II (rs37733634) gene polymorphisms with the development of idiopathic generalized epilepsy(Elsevier, 2014) Prasad, D.K.V.; Shaheen, U.; Satyanarayana, U.; Prabha, T.S.; Jyothy, A.; Munshi, A.The idiopathic generalized epilepsy (IGE) is a neurological disorder which accounts for approximately 30% of all epilepsy cases. Patients identified with IGE syndromes have pharmacoresponsive epilepsies without abnormal neurological symptoms, structural brain lesions and are of unknown origin. A genetic etiology to IGEs has been proposed. Gamma amino butyric acid (GABA), a major inhibitory neurotransmitter acts by binding to transmembrane GABAA and GABAB receptors of both pre- and postsynaptic neurons. Synapsin II (SynII), a neuron specific phosphoprotein plays a major role in synaptogenesis and neurotransmitter release. The present study was carried out with an aim to evaluate the association of GABRA6 (rs3219151) T>C and Syn II (rs37733634) A>G gene polymorphisms with IGE. Molecular analysis revealed that the frequency of 'CC' genotype and 'C'allele of GABRA6 (rs3219151) T>C gene polymorphism was significantly higher in IGE patients compared to healthy controls [CC vs. TT, ?2=26; p<0.001; Odds ratio=3.6 (95% CI; 2.1-5.9); C vs T, ?2=24.7; p<0.001; Odds ratio=1.78 (95% CI; 1.4-2.2)]. The frequency of 'GG' genotype and 'G' allele of the intronic polymorphism A>G in Syn II gene was also found to be significantly associated with the disease when compared to controls [GG vs AA, ?2=64.52; p<0.001; Odds ratio=7.37 (95% CI; 4.4-12.3); G vs. A, ?2=65.78; p<0.001; Odds ratio=2.57 (95% CI; 2.0-3.2)]. The generalized multifactor dimensionality reduction method was employed to detect gene-gene interactions. The gene-gene interaction at two loci involving GABRA6 and Syn II revealed a significant association [?2=36.6, p<0.001, Odds ratio=3.17 (95% CI; 2.2-4.6)] with IGE. Therefore, the present study clearly indicates that both GABRA6 (rs3219151) T>C and Syn II (rs37733634) A>G polymorphisms are important risk factors for the development of IGE in the South Indian population from Andhra Pradesh. The gene-gene interaction studies demonstrated significant interactive effects of these two loci in the development of the disease. ? 2014 Elsevier B.V.Item Association of the genetic variants of insulin receptor substrate 1 (IRS-1) with type 2 diabetes mellitus in a Saudi population(Humana Press Inc., 2014) Alharbi, Khalid Khalaf; Khan, Imran Ali; Munshi, Anjana; Alharbi, Fawiziah Khalaf; Al-Sheikh, Yazeed; Alnbaheen, May SalemType 2 diabetes mellitus (T2DM) is a chronic degenerative disease, phenotypically and genetically heterogeneous, characterized by high levels of glucose and metabolic complications. Insulin receptor substrate 1 (IRS-1) plays a key role in the insulin-stimulated signal transduction pathway. A glycine-to-arginine substitution at codon 972 (G972R) (rs1801278) in the IRS-1 gene has been associated with impaired insulin action. Another SNP rs2943641 in the IRS-1 gene has been found to be associated with T2DM and insulin resistance in genome-wide association studies. The aim of the present study was to evaluate whether rs1801278 and rs2943641 are associated with increased risk of T2DM in the Saudi population. The study included 376 T2DM cases and 380 healthy controls. Genomic DNA was isolated using a commercially available kit supplied by Norgen Biotech Corp. Genotyping was performed by PCR and RFLP analysis. There was a significant difference in the genotypic distribution as well as allelic frequency between the T2DM cases and controls in case of both the polymorphisms for rs1801278 (1.752, 95?% CI 1.002?3.121; p?=?0.04), and for rs2943641 (OR?=?1.482, 95?% CI 1.176?1.867; p?=?0.001). In conclusion, both the (rs1801278 and rs2943641) polymorphisms are associated with T2DM in the Saudi population. ? 2014, Springer Science+Business Media New York.Item Association of APOE (E2, E3 and E4) gene variants and lipid levels in ischemic stroke, its subtypes and hemorrhagic stroke in a South Indian population(Elsevier Ireland Ltd, 2016) Das, Satrupa; Kaul, Subhash; Jyothy, Akka; Munshi, AnjanaIn the present study we evaluated the association of APOE (E2/E3/E4) polymorphism with ischemic stroke (n = 620), its subtypes and hemorrhagic stroke (n = 250) in a South Indian population from Telangana. The genotypes were determined using PCR-RFLP while lipid levels were measured using commercially available kits. We found significant difference in the genotypic distribution between hemorrhagic stroke patients and controls for certain genetic models [E2/E2 vs. E2/E4; E3/E3 vs. E2/E3; E3/E3 vs. E2/E4; E4/E4 vs. E2/E3; E4/E4 vs.E2/E4 and E3 vs. E4]. However, no significant difference was observed in genotypic distribution between ischemic stroke patients and controls. On analysing the genotypic distribution between ischemic and hemorrhagic stroke patients, statistically significant difference was observed in specific genetic models [E2/E2 vs. E2/E4; E3/E3 vs. E2/E3; E3/E3 vs. E2/E4; E4/E4 vs. E2/E3 and E4/E4 vs. E2/E4]. In ischemic stroke subtypes analysing for alleles E3 vs. E2 and E3 vs. E4, we found significant association with intracranial large artery (p = 0.01), cardioembolic stroke (p = 0.001 and p = 0.0004) and lacunar stroke (p = 0.02). Analysing the association of various genotypes with different lipid levels significant association was observed for VLDL (P = 0.000) and for triglyceride (P = 0.000) levels with E2/E4 and E3/E4 genotypes in ischemic stroke but not in hemorrhagic stroke. In conclusion, our results suggest that APOE polymorphism does seem to play a role in hemorrhagic stroke and also in the development of specific subtypes of ischemic stroke. Further, in ischemic stroke VLDL and triglycerides levels were found to be significantly associated with E2/E4 and E3/E4 genotypes. ? 2016 Elsevier Ireland Ltd.Item A novel 7 bp deletion in PRPF31 associated with autosomal dominant retinitis pigmentosa with incomplete penetrance in an Indian family(2012) Saini, S.; Robinson, P.N.; Singh, J.R.; Vanita, V.To localize and identify the gene linked with non-syndromic autosomal dominant retinitis pigmentosa (adRP) with high but not complete penetrance in an Indian family. A detailed family history and clinical data were recorded. A genome-wide scan by 2-point linkage analysis using nearly 400 fluorescently labeled microsatellite markers in combination with multipoint lod score and haplotype analysis was carried out. Mutation screening was performed in the candidate gene by bidirectional sequence analysis of the amplified products. A maximum 2-point lod score of 3.553 at theta = 0.0 was obtained with marker D19S572. Haplotype analysis placed the RP locus distal to marker D19S572, in close proximity to the gene for pre-mRNA processing factor 31 (PRPF31) at 19q13.42. Mutation screening in all 14 exonic regions and adjacent flanking intronic sequences of PRPF31 revealed a novel 7 bp deletion, c.59_65del7 (p.Gly20AlafsX43), in the first coding exon of PRPF31. This leads to a premature termination codon (PTC) in the next exon, 43 amino acids downstream. The observed 7 bp deletion in PRPF31 was identified in all the tested 10 affected members and in an unaffected individual, consistent with a high, but not the complete penetrance of c.59_65del7 (p.Gly20AlafsX43). This deletion was not observed in other tested six unaffected family members or in 100 ethnically matched control subjects. The present study describes mapping of a locus for non-syndromic adRP at 19q13.42 (RP11 locus) in a family of Indian origin and identifies a novel deletion, c.59_65del7, in PRPF31 within the mapped interval. Since the mutant PRPF31 is truncated relatively close to the N-terminus of the protein, haploinsufficiency rather than aberrant protein formation is likely to be the underlying mechanism of the disease. The present findings further substantiate the role of PRPF31 that encodes a component of the spliceosome complex in relation to ADRP. ? 2012 Elsevier Ltd.