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Murthy J.,Sri Ramachandra University | Gurramkonda V.B.,Sri Ramachandra University | Lakkakula B.V.K.S.,Sri Ramachandra University | Lakkakula B.V.K.S.,Sickle Cell Institute Chhattisgarh
Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology

Objective: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common complex birth defect with complex etiology. Elevated levels of plasma homocysteine have been found to be associated with intrauterine growth retardation, preterm birth, intrauterine fetal death, neural tube defects and NSCL/P. The aim of the present study was to evaluate the role of A2756G SNP and MTRR A66G polymorphisms in the pathogenesis of NSCL/P in South Indian subjects. Methods: In the present study we genotyped MTR A2756G SNP and MTRR A66G polymorphisms in 142 patients with NSCL/P and 141 healthy controls using PCR-RFLP assay. Results: The genotype frequencies of the control group were in agreement with the Hardy-Weinberg equilibrium for the MTR A2756G (p= 0.096), but not for MTRR A66G (p< 0.001). The MTRR A66G is polymorphic, but the homozygous GG genotype was not observed in both control and NSCL/P groups. MTRR A66G heterozygous genotype significantly increased the risk of CL/P (OR = 1.65, 95% CI = 1.00-2.72) and CPO (OR = 3.21, 95% CI = 1.01-10.15) in codominant model suggesting a possible link with NSCL/P predisposition; however, the more stringent Yates' test suggests no significance. There are no clear differences in risk for CL/P or CPO was observed for different MTR- MTRR genotype combinations. Conclusions: The present study failed to show an association between the MTR A2756G gene and NSCL/P and provides possible evidence regarding MTRR A66G risk for non-syndromic cleft lip and palate possibly due to abnormal folate and homocysteine status in Indian population. © 2015 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Source

Murthy J.,Sri Ramachandra University | Venkatesh Babu G.Z.,Sri Ramachandra University | Bhaskar L.V.K.S.,Sri Ramachandra University | Bhaskar L.V.K.S.,Sickle Cell Institute Chhattisgarh
Malaysian Journal of Nutrition

Introduction: Non-syndromic cleft lip with or without cleft palate (NSCLP) is a multifactorial threshold trait (MFT) involving both genetic and environmental factors. Choline, methionine and folate metabolism are interrelated in converting the homocysteine to methionine. Phosphatidylethanolamine N-methyltransferase (PEMT) is involved in biosynthesis of choline. Methods: We studied the PEMT rs4244593 SNP to assess its effect on NSCLP risk in the South Indian population. Blood samples of 142 cases with NSCLP and 141 controls were collected and genotyped using PCR-RFLP. Statistical analysis of the results was performed by calculating OR, and 95% CI via x2 test. Results: Proportions of genotypes were 16.9 % AA,64.8 % AC,16.9 % CCincasesand35.5 % AA,47.5 % AC,17.0 % CC in controls. The C allele frequency was 50.7% for cases and 40.8% for controls. An increased risk was found for co-dominant (AC vs. AA: OR =2.86, 95% CI =1.60 to 5.11, p<0.001; CC vs. AA: OR =2.26, 95% CI =1.08 to 4.72, p=0.029), dominant (AC+CC vs. AA: OR =2.70, 95% CI =1.55 to 4.72, p<0.001) and allelic models (C vs. A: OR =1.49,95% CI =1.07 to 2.08, p=0.018). Conclusions: Although our results indicate that the PEMT rs4244.593 polymorphism is one of the important genetic determinants of NSCLP risk in South Indian subjects, in the absence of mechanistic studies, this polymorphism cannot be considered as a determinant of NSCLP risk. Additional studies with fully validated functional SNPs and larger sample sizes are needed to confirm our findings. Source

Murthy J.,Sri Ramachandra University | Gurramkonda V.-B.,Sri Ramachandra University | Lakkakula B.V.K.S.,Sri Ramachandra University | Lakkakula B.V.K.S.,Sickle Cell Institute Chhattisgarh
Medicina Oral, Patologia Oral y Cirugia Bucal

Objectives: Nonsyndromic cleft lip and palate (NSCLP) is genetically distinct from those with syndromic clefts, and accounts for ~70% of cases with Oral clefts. Folate, or vitamin B9, is an essential nutrient in our diet. Allelic variants in genes involved in the folate pathway might be expected to have an impact on risk of oral clefts. Given the key role of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) in folate metabolism, it would be of significant interest to assess its role in NSCLP etiology.Study Design: The present study aims at examining the association between MTHFD1 1958G>A polymorphism and NSCLP risk by conducting a case-control study in south Indian population. Our sample comprised of 142 cases with nonsyndromic clefts and 141 controls without clefts or family history of clefting. The MTHFD1 1958G>A polymorphism was genotyped using PCR-RFLP.Results: An increased risk was found for the heterozygous 1958GA (OR=2.44; P=0.020) and homozygous 1958AA (OR=2.45; P=0.012) genotypes in the children. When the dominant model (AG+AA vs GG) was applied the risk remained the same as co-dominant model, but the level of significance increased (OR=2.44; P=0.002).Conclusions: The results indicated the MTHFD1 1958G>A polymorphism to be one of the important genetic determinants of NSCLP risk in South Indian subjects. © Medicina Oral S. L. Source

Ramanathan G.,Sri Ramachandra University | Periyasamy S.,Sri Ramachandra University | Lakkakula B.V.,Sri Ramachandra University | Lakkakula B.V.,Sickle Cell Institute Chhattisgarh

Aim Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary and progressive renal disorder. It is also recognised as the most frequent genetic cause of chronic kidney diseases (CKD). In the present study, four tagging SNPs and two more well studied polymorphisms (Intron 4 VNTR and Glu298Asp) the NOS3 gene were investigated to unravel the potential modifier effect of NOS3 gene on the progression of CKD in ADPKD. Methods A total of 102 ADPKD patients and 106 controls were selected for the study. The tagSNPs and Glu298Asp polymorphisms were genotyped using FRET-based KASPar method and intron-4 VNTR by polymerase chain reaction electrophoresis. The genotypes and haplotypes in the controls and ADPKD subjects were analysed by χ2 tests and haploview software. Mantel-Haenszel stratified and univariate analyses were performed to estimate the influence of different genotypes between different CKD stages and hypertension. Results The tagSNPs of NOS3 genotypes and haplotypes did not exhibit any significant differences between controls and ADPKD patients. The significant linkage disequilibrium was observed between the rs3918184 and rs2853796 by forming LD block. In univariate analysis, the age and family history of Diabetes mellitus (DM) showed significant association with advancement of CKD, but not with the eNOS polymorphisms. Conclusions Our data suggests that there is no evidence for the involvement of NOS3 tag SNPs in the progression to CKD in ADPKD patients. A systematic study using well validated functional SNPs is necessary to clarify the role of the NOS3 gene in the development of CKD in ADPKD. Summary at a Glance The variability in progression to kidney failure in autosomal dominant polycystic kidney disease (ADPKD) could be explained, in part, by single nucleotide polymorphisms (SNPs) in candidate modifier genes. However, the results of the present study provide further evidence that SNPs in the NOS3 gene are not involved in the progression of ADPKD patients. © 2014 Asian Pacific Society of Nephrology. Source

Gnanasambandan R.,Sri Ramachandra University | Elumalai R.,Sri Ramachandra University | Soundararajan P.,Sri Ramachandra University | Lakkakula B.V.K.S.,Sri Ramachandra University | Lakkakula B.V.K.S.,Sickle Cell Institute Chhattisgarh
Clinical and Experimental Nephrology

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a multisystemic and progressive disorder characterized by cyst formation and kidney enlargement and ultimately renal failure. Reduction of CKD progression in the ADPKD by pharmacological blockade of the renin–angiotensin–aldosterone system (RAAS) using ACE inhibitors indicated the involvement of RAAS pathway in the progression of CKD. The aim of the present study is to investigate the role of angiotensinogen tag-single nucleotide polymorphisms (AGT tag-SNPs) in progression of CKD. Methods: Twelve AGT tag-SNPs were genotyped in 102 ADPKD patients and 106 non-ADPKD subjects using FRET-based KASPar method. Genotypes and haplotypes were compared between ADPKD and controls. The effect of genotypes and hypertension on CKD progression was assessed using univariate and multivariate logistic regression. Mantel–Haenszel (M–H) stratified analysis was performed to study the interaction between CKD stages and hypertension. Results: Of the twelve tag-SNPs analyzed, only rs11122578 SNP deviated Hardy–Weinberg equilibrium in controls. Significant association between two AGT polymorphisms (rs11122577 and rs4762) and ADPKD was observed. Analysis of linkage disequilibrium revealed two haplotype blocks and haplotypes are not associated with ADPKD. The univariate analysis revealed that the age, hypertension, family history of diabetes and AGT rs4762 contributed to the progression of CKD in ADPKD. The modifier effect of these factors remained even after controlling other variables in multivariate analysis. Conclusions: The results of our study suggest significant association between Thr207Met polymorphism of AGT and CKD progression and acts as an effect modifier of renal disease progression in ADPKD. © 2015 Japanese Society of Nephrology Source

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