Association of dopaminergic pathway gene polymorphisms with chronic renal insufficiency among Asian Indians with type-2 diabetes

<p>Abstract</p> <p>Background</p> <p>Genetic markers conferring susceptibility to diabetes specific renal disease remains to be identified for early prediction and development of effective drugs and therapies. Inconsistent results obtained from analysis of genes from classical pathways generate need for examination of unconventional genetic markers having role in regulation of renal function. Experimental and clinical evidences suggest that dopamine is an important natriuretic hormone. Therefore, various genes involved in regulation of dopamine bioavailability could play a role in diabetic chronic renal insufficiency (CRI). We investigated the contribution of 12 polymorphisms from five Dopaminergic pathway genes to CRI among type-2 diabetic Asian Indian subjects.</p> <p>Methods</p> <p>Genetic association of 12 polymorphisms (SNPs) from five genes namely-dopamine receptor-1 (<it>DRD1</it>), <it>DRD2</it>, <it>DRD3</it>, <it>DRD4</it>, andcatechol-O-methyltransferase (<it>COMT</it>) with diabetic CRI was investigated using a case-control approach. Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes.</p> <p>Results</p> <p>SNPs <it>-141 ins/del C and G>A </it>(1 kb upstream from exon 2) in DRD2 gene showed significant allelic and genotypic association. Allele <it>-141 insC </it>and genotype <it>-141 insC/insC </it>of <it>-141 ins/del C </it>polymorphism, and allele A of <it>G>A </it>SNP were found to be predisposing to CRI. Our result of allelic and genotypic association of -<it>141 insC/delC </it>SNP was also reflected in the haplotypic association. Heterozygous genotype of polymorphism <it>900 ins/del C in COMT </it>gene was predisposing towards CRI.</p> <p>Conclusion</p> <p>Some polymorphisms in <it>DRD2 </it>and <it>COMT </it>genes are significantly associated with susceptibility to CRI in the Asian Indian population which, if confirmed would be consistent with a suggested role of dopamine metabolism in disease occurrence.</p

Prevalence of Talon cusp in Indian population

Aim: To investigate the prevalence of the talon cusps in a sample of Indian dental patients and their distribution among different types of teeth. To determine the presence of other dental anomalies associated with the talon cusps. Methodology: 2740 out patients (1523 males and 1217 females) attending Oral Medicine department from November 2010 to January 2011 were screened for the presence of talon cusps and were subjected to Intra Oral Peri-apical (IOPA) radiograph to rule out any associated anomalies or peri-apical changes. Results: Talon cusps were detected in 16 out of 2740 patients (person prevalence 0.58%). Thirty one teeth were found to have talon cusp. Maxillary lateral incisors were the most commonly affected teeth (54.8%, 17 teeth), followed by maxillary central incisors and canines (16.12%, 5 teeth).Talon cusp was found in two mandibular central incisors (6.45%) and one each in mandibular second and third molar (3.22% each). Seventeen teeth in 7 patients (54.83%) were found to be associated with anomalies like dens invagination (6 teeth, 19.35%), impacted 13, 23 (6 teeth, 19.35%), partial anodontia (3 teeth, 9.67%), geographic and fissured tongue (2 teeth, 6.45%). Peri-apical granuloma was found in one tooth with talon cusp associated with dens invaginatus. None of the patients were found to be associated with any syndromes. Conclusion: Attention should be paid to the presence of the talon cusp and the associated anomalies. Early diagnosis of the talon cusp can help the clinician in preventing the further complications

Prevalence of type 1 diabetes mellitus in Karnal district, Haryana state, India

<p>Abstract</p> <p>Background</p> <p>Little work has been done on the prevalence of type 1 diabetes in north India. This paper reports the prevalence of type 1 diabetes in Karnal district of Haryana state, India.</p> <p>Materials and methods</p> <p>Prevalence of type 1 diabetes was assessed by a hospital-based registry and by analysis of data contributed by chemists and other physicians.</p> <p>Results</p> <p>The overall prevalence of type 1 diabetes in Karnal district is 10.20/100,000 population, with a higher prevalence in urban (26.6/100,000) as compared to rural areas (4.27/100,000). Karnal city, with a population of 222017, has a relatively high prevalence of type 1 diabetes (31.9/100,000). The prevalence in men is higher (11.56/100,000) than in women (8.6/100,000).</p> <p>In the 5 to 16 years age group, the prevalence is 22.22/100,000, while in the 0-5 years age group, prevalence is 3.82/100,000.</p> <p>Conclusions</p> <p>This report highlights the urban-rural and male-female gradient in the prevalence of type 1 diabetes in Karnal, north India.</p

Chronic renal insufficiency among Asian Indians with type 2 diabetes: I. Role of RAAS gene polymorphisms

BACKGROUND: Renal failure in diabetes is mediated by multiple pathways. Experimental and clinical evidences suggest that renin-angiotensin-aldosterone system (RAAS) has a crucial role in diabetic kidney disease. A relationship between the RAAS genotypes and chronic renal insufficiency (CRI) among type 2 diabetes subjects has therefore been speculated. We investigated the contribution of selected RAAS gene polymorphisms to CRI among type 2 diabetic Asian Indian subjects. METHODS: Twelve single nucleotide polymorphisms (SNPs) from six genes namely-renin (REN), angiotensinogen (ATG), angiotensin converting enzyme I (ACE), angiotensin II type 1 receptor (AT1) and aldosterone synthase (CYP11B2) gene from the RAAS pathway and one from chymase pathway were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and tested for their association with diabetic CRI using a case-control approach. Successive cases presenting to study centres with type 2 diabetes of ≥2 years duration and moderate CRI diagnosed by serum creatinine ≥3 mg/dl after exclusion of non-diabetic causes of CRI (n = 196) were compared with diabetes subjects with no evidence of renal disease (n = 225). Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes. RESULTS: Of the 12 SNPs genotyped, Glu53Stop in AGT and A>T (-777) in AT1 genes, were monomorphic and not included for further analysis. We observed a highly significant association of Met235Thr SNP in angiotensinogen gene with CRI (O.R. 2.68, 95%CI: 2.01–3.57 for Thr allele, O.R. 2.94, 95%CI: 1.88–4.59 for Thr/Thr genotype and O.R. 2.68, 95%CI: 1.97–3.64 for ACC haplotype). A significant allelic and genotypic association of T>C (-344) SNP in aldosterone synthase gene (O.R. 1.57, 95%CI: 1.16–2.14 and O.R. 1.81, 95%CI: 1.21–2.71 respectively), and genotypic association of GA genotype of G>A (-1903) in chymase gene (O.R. 2.06, 95%CI: 1.34–3.17) were also observed. CONCLUSION: SNPs Met235Thr in angiotensinogen, T>C (-344) in aldosterone synthase, and G>A (-1903) in chymase genes are significantly associated with diabetic chronic renal insufficiency in Indian patients and warrant replication in larger sample sets. Use of such markers for prediction of susceptibility to diabetes specific renal disease in the ethnically Indian population appears promising

Association of TGFβ1, TNFα, CCR2 and CCR5 gene polymorphisms in type-2 diabetes and renal insufficiency among Asian Indians

BACKGROUND: Cytokines play an important role in the development of diabetic chronic renal insufficiency (CRI). Transforming growth factor β1 (TGF β1) induces renal hypertrophy and fibrosis, and cytokines like tumor necrosis factor-alpha (TNFα), chemoattractant protein-1 (MCP-1), and regulated upon activation and normal T cell expressed and secreted (RANTES) mediate macrophage infiltration into kidney. Over expression of these chemokines leads to glomerulosclerosis and interstitial fibrosis. The effect of MCP-1 and RANTES on kidney is conferred by their receptors i.e., chemokine receptor (CCR)-2 and CCR-5 respectively. We tested association of nine single nucleotide polymorphisms (SNPs) from TGFβ1, TNFα, CCR2 and CCR5 genes among individuals with type-2 diabetes with and without renal insufficiency. METHODS: Type-2 diabetes subjects with chronic renal insufficiency (serum creatinine ≥ 3.0 mg/dl) constituted the cases, and matched individuals with diabetes of duration ≥ 10 years and normoalbuminuria were evaluated as controls from four centres in India. Allelic and genotypic contributions of nine SNPs from TGFβ1, TNFα, CCR2 and CCR5 genes to diabetic CRI were tested by computing odds ratio (OR) and 95% confidence intervals (CI). Sub-analysis of CRI cases diabetic retinopathy status as dependent variable and SNP genotypes as independent variable in a univariate logistic regression was also performed. RESULTS: SNPs Tyr81His and Thr263Ile in TGF β1 gene were monomorphic, and Arg25Pro in TGF β1 gene and Δ32 polymorphism in CCR5 gene were minor variants (minor allele frequency <0.05) and therefore were not considered for case-control analysis. A significant allelic association of 59029G>A SNP of CCR5 gene has been observed and the allele 59029A seems to confer predisposition to development of diabetic CRI (OR 1.39; CI 1.04–1.84). In CRI subjects a compound group of genotypes "GA and AA" of SNP G>A -800 was found to confer predisposition for proliferative retinopathy (OR 3.03; CI 1.08–8.50, p = 0.035). CONCLUSION: Of the various cytokine gene polymorphisms tested, allele 59029A of CCR5 gene is significantly associated with diabetic renal insufficiency among Asian Indians. Result obtained for 59029G>A SNP of CCR5 gene is in conformity with reports from a Japanese population but due to sub-optimal power of the sample, replication in larger sample set is warranted

Association analysis of ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 gene polymorphisms with chronic renal insufficiency among Asian Indians with type-2 diabetes

<p>Abstract</p> <p>Background</p> <p>To determine association of nine single nucleotide polymorphisms (SNPs) in ADP ribosyltransferase-1 (ADPRT1), aldo-keto reductase family 1 member B1 (AKR1B1), receptor for advanced glycation end-products (RAGE), glutamine:fructose-6-phosphate amidotransferase-2 (GFPT2), and plasminogen activator inhibitor-1 (PAI-1) genes with chronic renal insufficiency (CRI) among Asian Indians with type 2 diabetes; and to identify epistatic interactionss between genes from the present study and those from renin-angiotensin-aldosterone system (RAAS), and chemokine-cytokine, dopaminergic and oxidative stress pathways (previously investigated using the same sample set).</p> <p>Methods</p> <p>Type 2 diabetes subjects with CRI (serum creatinine ≥3.0 mg/dl) constituted the cases (n = 196), and ethnicity and age matched individuals with diabetes for a duration of ≥ 10 years, normal renal functions and normoalbuminuria recruited as controls (n = 225). Allelic and genotypic constitution of 10 polymorphisms (SNPs) from five genes namely- <it>ADPRT1</it>, <it>AKR1B1, RAGE, GFPT2 </it>and <it>PAI-1 </it>with diabetic CRI was investigated. The genetic associations were evaluated by computation of odds ratio and 95% confidence interval. Multiple logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study epistatic interactions between SNPs in different genes.</p> <p>Results</p> <p>Single nucleotide polymorphisms -429 T>C in <it>RAGE </it>and rs7725 C>T SNP in 3' UTR in <it>GFPT2 </it>gene showed a trend towards association with diabetic CRI. Investigation using miRBase statistical tool revealed that rs7725 in <it>GFPT2 </it>was a perfect target for predicted miRNA (hsa miR-378) suggesting the presence of the variant 'T' allele may result in an upregulation of GFPT2 contributing to diabetic renal complication. Epistatic interaction between SNPs in transforming growth factor <it>TGF-β1 </it>(investigated using the same sample set and reported elsewhere) and <it>GFPT2 </it>genotype was observed.</p> <p>Conclusions</p> <p>Association of SNPs in <it>RAGE </it>and <it>GFPT2 </it>suggest that the genes involved in modulation of oxidative pathway could be major contributor to diabetic chronic renal insufficiency. In addition, GFPT2 mediated overproduction of TGF-β1 leading to endothelial expansion and thereby CRI seems likely, suggested by our observation of a significant interaction between GFPT2 with TGF-β1 genes. Further, identification of predicted miRNA targets spanning the associated SNP in <it>GFPT2 </it>implicates the rs7725 SNP in transcriptional regulation of the gene, and suggests <it>GFPT2 </it>could be a relevant target for pharmacological intervention. Larger replication studies are needed to confirm these observations.</p

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV