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Estudo de associação entre genes do sistema dopaminérgico e esquizofrenia; Study of association between genes of the dopaminergic system and schizophrenia

Cordeiro Junior, Quirino
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 16/08/2007 Português
Relevância na Pesquisa
16.85%
Evidências de estudos genético-epidemiológicos têm demonstrado a existência de um fator de risco genético para o desenvolvimento da esquizofrenia. Na presente Tese, um total de 245 pacientes com esquizofrenia e 834 controles foi selecionado com o objetivo de investigar a diferença na distribuição de alelos e genótipos de seis polimorfismos de quatro diferentes genes do sistema dopaminérgico nesses dois grupos: 1. TaqI A1/A2 do DRD2 - rs1800497; 2. -141C (Ins/Del) do DRD2 - rs1799732; 3. Ser-9-Gly do DRD3 - rs6280; 4. VNTR da região 3´ não-codificadora do SLC6A3; 5. A1343G do SLC6A3 - rs6347; 6. A/G da região 3´ não-codificadora do COMT - rs165599. Os resultados mostraram associação dos polimorfismos -141C (Ins/Del) do DRD2 (rs1799732) e A1343G do SLC6A3 (rs6347) com esquizofrenia na amostra investigada.; Evidences from genetic epidemiological studies have demonstrated the existence of a genetic risk factor for schizophrenia. In the present work a total of 245 schizophrenic patients and 834 controls were selected to investigate differences in the allelic and genotypic distribution of six polymorphisms from four different genes of the dopaminergic system between the groups: 1. TaqI A1/A2 of the DRD2 - rs1800497; 2. -141C (Ins/Del) of the DRD2 - rs1799732; 3. Ser-9-Gly of the DRD3 - rs6280; 4. VNTR in the 3'-untranslated region of the SLC6A3; 5. A1343G of the SLC6A3 - rs6347; 6. A/G in the 3'-untranslated region of the COMT - rs165599. The results have found an association of the polymorphisms -141C (Ins/Del) of the DRD2 (rs1799732) and A1343G of the SLC6A3 (rs6347) with schizophrenia in the investigated sample.

Análise das repetições CA do gene IGF1, VNTR do gene da insulina e região promotora P4 do gene IGF2 em indivíduos nascidos pequenos para idade gestacional; Analysis of the CA repeats of IGF1 gene, VNTR of insulin gene polymorphism and P4 Promoter region of IGF2 gene in children born small for gestational age

Coletta, Rocio Riatto Della
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 22/02/2008 Português
Relevância na Pesquisa
37.35%
Introdução: Polimorfismos na região promotora dos genes da insulina, IGF2 e IGF1 podem estar relacionados a uma diminuição da expressão desses genes na vida fetal que, por sua vez, pode causar restrição do crescimento intra-uterino e maior risco de hipospádia. Na vida pós-natal, perda completa ou parcial da expressão desses genes pode resultar em ausência de recuperação estatural e menores concentrações séricas de IGF1 na criança, além de um maior risco de diabetes melito tipo 2 e síndrome de resistência à insulina no adulto. Objetivos: Analisar em crianças nascidas pequenas para idade gestacional (PIG) com ou sem recuperação estatural (RE): 1) a freqüência alélica e genotípica dos polimorfismos VNTR-INS e das repetições CA do gene IGF1; 2) a região promotora P4 do gene IGF2; 3) a influência do VNTR INS e das repetições CA do gene IGF1 na sensibilidade à insulina e nas concentrações séricas de IGF1, respectivamente. Pacientes: Foram estudados 142 indivíduos nascidos PIG com (n= 66) e sem recuperação (n= 76) estatural selecionados de três diferentes centros (HC-FMUSP, Santa Casa de São Paulo e HC-UFPR) e um grupo controle constituído de 297 indivíduos nascidos adequados para idade gestacional (AIG). Métodos: Extração de DNA genômico; amplificação por PCR das regiões contendo os polimorfismos VNTR INS e repetições CA do IGF1 e da região promotora P4; digestão por enzima de restrição; software Genescan; seqüenciamento automático; avaliação bioquímica e hormonal da glicemia...

Associação do polimorfismo INS-VNTR com a susceptibilidade ao diabetes mellitus tipo 1, tipo 2 e gestacional na população urbana brasileira; Association of the INS-VNTR polymorphism with susceptibility to type 1, type 2 and gestational diabetes mellitus in the urban brazilian population

Pelá, Flávia Porto
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 19/10/2012 Português
Relevância na Pesquisa
67.4%
O diabetes mellitus (DM) é definido como doença metabólica, caracterizado pela hiperglicemia, causada pela disfunção da secreção de insulina, atividade da insulina ou ambas. É classificado em quatro classes clínicas i) diabetes mellitus tipo 1 (DM1), ii) diabetes mellitus tipo 2 (DM2), iii) diabetes mellitus gestacional (DMG), iv) outros tipos específicos. Dentre os genes conhecidos por influenciarem o mecanismo de produção e liberação de insulina no organismo humano, o gene da insulina (INS) é o mais bem caracterizado nas classes clínicas do DM. A região promotora do gene INS tem sido alvo de estudo em diversas amostras populacionais do mundo, devido a sua capacidade de modular os níveis de expressão de insulina no timo e no pâncreas, de acordo, com a classe alélica que compõe o genótipo do indivíduo. Localizada a 596pb acima do sítio de transcrição do gene da insulina, é estruturada em alelos minissatélites distribuídos in tandem (ACAGGGGTGTGGGG). O alelo classe I (30 - 60 repetições) tem sido associado com predisposição ao DM1, enquanto o alelo classe III (120 - 170 repetições) tem efeito de proteção ao DM1, no entanto, esse alelo tem apresentado correlação ao DM2, à obesidade em crianças e jovens e...

Investigação de genes envolvidos no controle da ingestão alimentar em estudos de associação com fenótipos relacionados à obesidade humana

Jaeger, Janaína Pacheco
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Tese de Doutorado Formato: application/pdf
Português
Relevância na Pesquisa
16.67%
O aumento da prevalência de obesidade em várias regiões do planeta vem se revelando como um dos mais importantes fenômenos clínico-epidemiológicos da atualidade. Fatores como a mudança do hábito alimentar e o estilo de vida sedentário, aliados a determinantes genéticos ainda pouco conhecidos, desempenham um papel relevante na patogênese desta doença. Nos últimos dez anos, desde o descobrimento do hormônio leptina, avanços consideráveis foram obtidos na caracterização dos mecanismos hipotalâmicos do controle da ingestão alimentar. Tais avanços têm revelado as particularidades de um sistema complexo e integrado, e têm oferecido novas perspectivas para abordagens terapêuticas específicas. Apesar da contribuição de fatores genéticos no desenvolvimento do ganho de peso ser amplamente reconhecida, a real contribuição quantitativa dos mesmos em fenótipos relacionados é ainda uma questão complexa que precisa ser esclarecida. Na presente Tese, foram avaliados onze polimorfismos em oito genes candidatos e suas possíveis influências sobre parâmetros de massa e de distribuição da gordura corporal em uma amostra da população da região metropolitana de Porto Alegre de ancestralidade predominantemente européia. Foram analisados polimorfismos localizados nos seguintes genes candidatos à obesidade: Proteína relacionada a agouti (AgRP)...

PCR-based VNTR core sequence analysis for inferring genetic diversity in the shrimp Litopenaeus vannamei

Freitas,Patrícia Domingues de; Galetti Junior,Pedro Manoel
Fonte: Sociedade Brasileira de Genética Publicador: Sociedade Brasileira de Genética
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2002 Português
Relevância na Pesquisa
36.58%
The genetic variation in two farmed strains (F3-Panama and F17-Venezuela) of the shrimp Litopenaeus vannamei was examined based on DNA multiloci analyses. Eighteen adults of each strain were analyzed by PCR using a set of VNTR core sequence primers. Genetic similarity, mean allele frequency, mean heterozygosity and the frequency of polymorphic loci were determined for both strains. A dendrogram of genetic similarity was produced by UPGMA clustering. The results for three primers (INS, M13, YN73) revealed different levels of genetic variation within the strains. The higher genetic similarity seen within strain F17 was apparently related to inbreeding, although a bottleneck effect could not be discarded. The low level of genetic variability of this strain could account for the reduced adaptive advantage of these animals and their inability to adjust to breeding conditions in Brazil.

Structural Analysis of Insulin Minisatellite Alleles Reveals Unusually Large Differences in Diversity between Africans and Non-Africans

Stead, John D. H.; Jeffreys, Alec J.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
26.21%
The insulin minisatellite (INS VNTR) associates with susceptibility to a variety of diseases. We have developed a high-resolution system for analyzing variant repeat distributions applicable to all known minisatellite alleles, irrespective of size, which allows lineages of related alleles to be identified. This system has previously revealed extremely low structural diversity in the minisatellite among northern Europeans from the United Kingdom, with all alleles belonging to one of only three highly diverged lineages called “I,” “IIIA,” and “IIIB.” To explore the origins of this remarkably limited lineage diversity, we have characterized an additional 780 alleles from three non-African and three African populations. In total, 22 highly diverged lineages were identified, with structural intermediates absent from extant populations, suggesting a bottleneck within the ancestry of all humans. The difference between levels of diversity in Africans and non-Africans is unusually large, with all 22 lineages identified in Africa compared with only three lineages seen not only in the United Kingdom but also in the other non-African populations. We also find evidence for overrepresentation of lineage I chromosomes in non-Africans. These data are consistent with a common out-of-Africa origin and an unusually tight bottleneck within the ancestry of all non-African populations...

Global Haplotype Diversity in the Human Insulin Gene Region

Stead, John D.H.; Hurles, Matthew E.; Jeffreys, Alec J.
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /09/2003 Português
Relevância na Pesquisa
26.21%
The insulin minisatellite (INS VNTR) has been intensively analyzed due to its associations with diseases including diabetes. We have previously used patterns of variant repeat distribution in the minisatellite to demonstrate that genetic diversity is unusually great in Africans compared to non-Africans. Here we analyzed variation at 56 single nucleotide polymorphisms (SNPs) flanking the minisatellite in individuals from six populations, and we show that over 40% of the total genetic variance near the minisatellite is due to differences between Africans and non-Africans, far higher than seen in most genomic regions and consistent with differential selection acting on the insulin gene region, most likely in the non-African ancestral population. Linkage disequilibrium was lower in African populations, with evidence of clustering of historical recombination events. Analysis of haplotypes from the relatively nonrecombining region around the minisatellite revealed a star-shaped phylogeny with lineages radiating from an ancestral African-specific haplotype. These haplotypes confirmed that minisatellite lineages defined by variant repeat distributions are monophyletic in origin. These analyses provide a framework for a cladistic approach to future disease association studies of the insulin region within both African and non-African populations...

Two-locus maximum lod score analysis of a multifactorial trait: joint consideration of IDDM2 and IDDM4 with IDDM1 in type 1 diabetes.

Cordell, H J; Todd, J A; Bennett, S T; Kawaguchi, Y; Farrall, M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1995 Português
Relevância na Pesquisa
26.21%
To investigate the genetic component of multifactorial diseases such as type 1 (insulin-dependent) diabetes mellitus (IDDM), models involving the joint action of several disease loci are important. These models can give increased power to detect an effect and a greater understanding of etiological mechanisms. Here, we present an extension of the maximum lod score method of N. Risch, which allows the simultaneous detection and modeling of two unlinked disease loci. Genetic constraints on the identical-by-descent sharing probabilities, analogous to the "triangle" restrictions in the single-locus method, are derived, and the size and power of the test statistics are investigated. The method is applied to affected-sib-pair data, and the joint effects of IDDM1 (HLA) and IDDM2 (the INS VNTR) and of IDDM1 and IDDM4 (FGF3-linked) are assessed with relation to the development of IDDM. In the presence of genetic heterogeneity, there is seen to be a significant advantage in analyzing more than one locus simultaneously. Analysis of these families indicates that the effects at IDDM1 and IDDM2 are well described by a multiplicative genetic model, while those at IDDM1 and IDDM4 follow a heterogeneity model.

CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers

VAN DER AUWERA, B J; VANDEWALLE, C L; SCHUIT, F C; WINNOCK, F; DE LEEUW, I H; VAN IMSCHOOT, S; LAMBERIGTS, G; GORUS, F K;
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em /10/1997 Português
Relevância na Pesquisa
26.97%
Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5′ region of the insulin gene (INS VNTR, IDDM2), several other loci have been proposed to contribute to IDDM susceptibility. Recently, linkage and association have been shown between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene on chromosome 2q and IDDM. In a registry-based group of 525 recent-onset IDDM patients < 40 years old we investigated the possible interactions of a CTLA-4 gene A-to-G transition polymorphism with age at clinical disease onset and with the presence or absence of established genetic (HLA-DQ, INS VNTR) and immune disease markers (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65-Ab); IA-2 protein tyrosine phosphatase (IA-2-Ab)) determined within the first week of insulin treatment. In new-onset IDDM patients, G-allele-containing CTLA-4 genotypes (relative risk (RR) = 1.5; 95% confidence interval (CI) = 1.2–2.0; P< 0.005) were not preferentially associated with age at clinical presentation or with the presence of other genetic (HLA-DR3 or DR4 alleles; HLA-DQA1*0301-DQB1*0302 and/or DQA1*0501-DQB1*0201 risk haplotypes; INS VNTR I/I risk genotype) or immune (ICA...

Autoimmune responses to the β cell autoantigen, insulin, and the INS VNTR-IDDM2 locus

SARUGERI, E; DOZIO, N; BELLONI, C; MESCHI, F; PASTORE, M R; BONIFACIO, E
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Publicado em /12/1998 Português
Relevância na Pesquisa
47.28%
Type 1 diabetes is associated with autoimmunity to insulin. Genetic susceptibility to type 1 diabetes is polygenic and includes the INS VNTR-IDDM2 locus which may regulate the expression of insulin in pancreas and thymus. In order to determine whether insulin autoimmunity could be attributed to a genetic susceptibility conferred by the INS VNTR-IDDM2 locus, peripheral blood T cell proliferation to human insulin and insulin autoantibodies (IAA) was measured in patients with new onset type 1 diabetes and control subjects. IAA were detected in 21 of 53 patients and in none of 25 control subjects, while T cell responses were low (stimulation index range 0.4–7.2) and similar in both groups. Both antibody and T cell responses were higher in younger subjects and IAA were more prevalent in patients with the HLA-DR4 allele. No relationship was observed between humoral and cellular responses to insulin. No association was found between the INS VNTR-IDDM2-susceptible allele and insulin autoimmunity. Increased T cell responses and IAA were found in patients with either the diabetes-susceptible or the diabetes-protective INS VNTR-IDDM2 locus genotypes, and increased T cell responses were also found in control subjects with either susceptible or protective INS VNTR-IDDM2 locus genotypes. This study confirms that primary T cell proliferative responses to insulin are low and detectable also in control subjects. The detection of T cell proliferation and autoantibodies to insulin in subjects with and without the protective INS VNTR-IDDM2 locus genotypes does not support the hypothesis of an allele-specific capacity for tolerance induction which could determine a susceptibility to develop autoimmunity against the insulin protein and subsequently diabetes.

Common polymorphic variation in the genetically diverse African insulin gene and its association with size at birth

Petry, Clive J.; Rayco-Solon, Pura; Fulford, Anthony J. C.; Stead, John D. H.; Wingate, Dianne L.; Ong, Ken K.; Sirugo, Giorgio; Prentice, Andrew M.; Dunger, David B.
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
27.1%
The insulin variable number of tandem repeats (INS VNTR) has been variably associated with size at birth in non-African populations. Small size at birth is a major determinant of neonatal mortality, so the INS VNTR may influence survival. We tested the hypothesis, therefore, that genetic variation around the INS VNTR in a rural Gambian population, who experience seasonal variation in nutrition and subsequently birth weight, may be associated with foetal and early growth. Six polymorphisms flanking the INS VNTR were genotyped in over 2,500 people. Significant associations were detected between the maternally inherited SNP 27 (rs689) allele and birth length [effect size 17.5 (5.2–29.8) mm; P = 0.004; n = 361]. Significant associations were also found between the maternally inherited African-specific SNP 28 (rs5506) allele and post-natal weight gain [effect size 0.19 (0.05–0.32) z score points/year; P = 0.005; n = 728). These results suggest that in the Gambian population studied there are associations between polymorphic variation in the genetically diverse INS gene and foetal and early growth characteristics, which contribute to overall polygenic associations with these traits.

Approaches in type 1 diabetes research: A status report

Raha, Oindrila; Chowdhury, Subhankar; Dasgupta, Samir; Raychaudhuri, P.; Sarkar, B. N.; Raju, P. Veer; Rao, V. R.
Fonte: Medknow Publications Publicador: Medknow Publications
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
Relevância na Pesquisa
26.21%
Type 1 diabetes is a multifactorial disease with an early age of onset, in which the insulin producing β cell of the pancreas are destroyed because of autoimmunity. It is the second most common chronic disease in children and account for 5% to 10% of all diagnosed cases of diabetes. India is having an incidence of 10.6 cases/year/100,000, and recent studies indicate that the prevalence of type 1 diabetes in India is increasing. However in view of poor health care network, there is no monitoring system in the country. Of the 18 genomic intervals implicated for the risk to develop type 1 diabetes, the major histocompatibility complex (MHC) region on chromosome 6p21.31 has been the major contributor estimated to account for 40-50%, followed by 10% frequency of INS-VNTR at 5’ flanking region of the insulin gene on chromosome 11p15.5. However, population studies suggest that > 95% of type 1 diabetes have HLA-DR3 or DR4, or both, and in family studies, sibling pairs affected with type 1 diabetes have a non-random distribution of shared HLA haplotypes. As predisposing genetic factors such as HLA alleles are known, immunological interventions to prevent type 1 diabetes are of great interest. In the present study we have reviewed the status of molecular genetics of the disease and the approaches that need to be adopted in terms of developing patient and suitable control cohorts in the country.

Prenatal Famine and Genetic Variation Are Independently and Additively Associated with DNA Methylation at Regulatory Loci within IGF2/H19

Tobi, Elmar W.; Slagboom, P. Eline; van Dongen, Jenny; Kremer, Dennis; Stein, Aryeh D.; Putter, Hein; Heijmans, Bastiaan T.; Lumey, L. H.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 30/05/2012 Português
Relevância na Pesquisa
26.85%
Both the early environment and genetic variation may affect DNA methylation, which is one of the major molecular marks of the epigenome. The combined effect of these factors on a well-defined locus has not been studied to date. We evaluated the association of periconceptional exposure to the Dutch Famine of 1944–45, as an example of an early environmental exposure, and single nucleotide polymorphisms covering the genetic variation (tagging SNPs) with DNA methylation at the imprinted IGF2/H19 region, a model for an epigenetically regulated genomic region. DNA methylation was measured at five differentially methylated regions (DMRs) that regulate the imprinted status of the IGF2/H19 region. Small but consistent differences in DNA methylation were observed comparing 60 individuals with periconceptional famine exposure with unexposed same-sex siblings at all IGF2 DMRs (PBH<0.05 after adjustment for multiple testing), but not at the H19 DMR. IGF2 DMR0 methylation was associated with IGF2 SNP rs2239681 (PBH = 0.027) and INS promoter methylation with INS SNPs, including rs689, which tags the INS VNTR, suggesting a mechanism for the reported effect of the VNTR on INS expression (PBH = 3.4×10−3). Prenatal famine and genetic variation showed similar associations with IGF2/H19 methylation and their contributions were additive. They were small in absolute terms (<3%)...

Assessment of Type 1 Diabetes Risk Conferred by HLA-DRB1, INS-VNTR and PTPN22 Genes Using the Bayesian Network Approach

Portuesi, Rosalba; Pozzilli, Paolo; Boehm, Bernhard; Buzzetti, Raffaella; Filippi, Simonetta
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 18/11/2013 Português
Relevância na Pesquisa
26.21%

Avidity-Dependent Programming of Autoreactive T Cells in T1D

Durinovic-Belló, Ivana; Gersuk, Vivian H.; Ni, Chester; Wu, Rebecca; Thorpe, Jerill; Jospe, Nicholas; Sanda, Srinath; Greenbaum, Carla J.; Nepom, Gerald T.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 20/05/2014 Português
Relevância na Pesquisa
26.42%
Fate determination for autoreactive T cells relies on a series of avidity-dependent interactions during T cell selection, represented by two general types of signals, one based on antigen expression and density during T cell development, and one based on genes that interpret the avidity of TCR interaction to guide developmental outcome. We used proinsulin-specific HLA class II tetramers to purify and determine transcriptional signatures for autoreactive T cells under differential selection in type 1 diabetes (T1D), in which insulin (INS) genotypes consist of protective and susceptible alleles that regulate the level of proinsulin expression in the thymus. Upregulation of steroid nuclear receptor family 4A (NR4A) and early growth response family genes in proinsulin-specific T cells was observed in individuals with susceptible INS-VNTR genotypes, suggesting a mechanism for avidity-dependent fate determination of the T cell repertoire in T1D. The NR4A genes act as translators of TCR signal strength that guide central and peripheral T cell fate decisions through transcriptional modification. We propose that maintenance of an NR4A-guided program in low avidity autoreactive T cells in T1D reflects their prior developmental experience influenced by proinsulin expression...

A Genome-Wide Assessment of the Role of Untagged Copy Number Variants in Type 1 Diabetes

Zanda, Manuela; Onengut-Gumuscu, Suna; Walker, Neil; Shtir, Corina; Gallo, Daniel; Wallace, Chris; Smyth, Deborah; Todd, John A.; Hurles, Matthew E.; Plagnol, Vincent; Rich, Stephen S.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 29/05/2014 Português
Relevância na Pesquisa
26.67%
Genome-wide association studies (GWAS) for type 1 diabetes (T1D) have successfully identified more than 40 independent T1D associated tagging single nucleotide polymorphisms (SNPs). However, owing to technical limitations of copy number variants (CNVs) genotyping assays, the assessment of the role of CNVs has been limited to the subset of these in high linkage disequilibrium with tag SNPs. The contribution of untagged CNVs, often multi-allelic and difficult to genotype using existing assays, to the heritability of T1D remains an open question. To investigate this issue, we designed a custom comparative genetic hybridization array (aCGH) specifically designed to assay untagged CNV loci identified from a variety of sources. To overcome the technical limitations of the case control design for this class of CNVs, we genotyped the Type 1 Diabetes Genetics Consortium (T1DGC) family resource (representing 3,903 transmissions from parents to affected offspring) and used an association testing strategy that does not necessitate obtaining discrete genotypes. Our design targeted 4,309 CNVs, of which 3,410 passed stringent quality control filters. As a positive control, the scan confirmed the known T1D association at the INS locus by direct typing of the 5′ variable number of tandem repeat (VNTR) locus. Our results clarify the fact that the disease association is indistinguishable from the two main polymorphic allele classes of the INS VNTR...

Lack of association of INS VNTR polymorphism with polycystic ovary syndrome: a meta-analysis

Song, Liu-ying; Luo, Jing-rong; Peng, Qi-liu; Wang, Jian; Xie, Li; He, Yu; Li, Shan; Qin, Xue
Fonte: Springer US Publicador: Springer US
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
26.21%

The Genetic Profile from HLA and Non-HLA Loci Allows Identification of Atypical Type 2 Diabetes Patients

Fabregat, Matias; Fernandez, Mariana; Javiel, Gerardo; Vitarella, Graciela; Mimbacas, Adriana
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
26.21%
The complex diagnosis and treatment of diabetes highlight the need for markers to define how to monitor patients correctly during the course of their disease. Different studies demonstrate the existence of patients who cannot be clearly classified. We have previously shown that it is possible to differentiate “atypical diabetic patients” based on genotyping the HLA. In this work we show that the analysis of non-HLA related to type 1 diabetes in the INS-VNTR, SNP rs689, and rs3842753 improves the identification of these patients. We genotyped 913 individuals comprising controls from the general population and “classic” and “atypical” diabetic patients. We compared the distribution of these loci and analyzed linkage disequilibrium. The haplotype was in LD for all the SNPs that were evaluated. Regarding their association with the disease, the haplotype IAC was associated with type 1 (odds 2.60, 1.82–3.72, CI 95%) and “atypical diabetes” (odds 1.50, 1.01–2.23, CI 95%), whereas we did not observe an association with type 2 diabetes. Therefore, our results confirm that atypical diabetes is a different entity of the disease where the patient presents with a genetic background of T1D and a T2D phenotype, findings that are likely to be relevant for patient diagnosis and management in the clinic.

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Durinovic-Belló, I; Wu, R P; Gersuk, V H; Sanda, S; Shilling, H G; Nepom, G T
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.79%
Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4+ proinsulin (PI) 76–90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex class II tetramers. Subjects with type I diabetes and healthy controls with high levels of peripheral proinsulin-specific T cells were characterized by the presence of a disease-susceptible polymorphism in the insulin variable number of tandem repeats (INS-VNTR) gene. Conversely, subjects with a ‘protective' polymorphism in the INS-VNTR gene had nearly undetectable levels of proinsulin tetramer-positive T cells. These results strongly imply a direct relationship between genetic control of autoantigen expression and peripheral autoreactivity, in which proinsulin genotype restricts the quantity and quality of the potential T-cell response. Using a modified tetramer to isolate low-avidity proinsulin-specific T cells from subjects with the susceptible genotype, transcript arrays identified several induced pro-apoptotic genes in the control, but not diabetic subjects, likely representing a second peripheral mechanism for maintenance of tolerance to self antigens.

Insulin gene VNTR genotype is associated with insulin sensitivity and secretion in infancy

Mericq Guila, María Verónica; Ong, Ken; Dunger, D. B.; Petry, C. J.; Avila, Alejandra; Bazaes Castillo, Rodrigo Antonio
Fonte: BLACKWELL PUBLISHING Publicador: BLACKWELL PUBLISHING
Tipo: Artículo de revista
Português
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36.98%
AIMS We have previously demonstrated that insulin sensitivity and secretion at age 1 year was in part related to variation in weight and height gain during infancy. In order to determine whether genetic variation at the insulin gene could also influence these associations, we have studied the relationship between insulin gene variable number of tandem repeat (INS VNTR) genotypes, insulin secretion and early postnatal growth. METHODS We assessed fasting and dynamic insulin secretion in 99 healthy infants at age 1 year, using a short intravenous glucose tolerance test (sIVGTT). Infants were genotyped at the -23 HphI locus, as a surrogate marker for INS VNTR allele classes I and III. Anthropometric data were recorded at birth and at 1 year. Data are shown as median (interquartile range). RESULTS Fasting insulin levels were higher in III/III infants (n = 9) than in I/I infants [n = 55; 27.4 (17.6-75.6) pmol/l vs. 18.1 (10.3-25.2) pmol/l; P < 0.05]. Insulin secretion during the sIVGTT, as estimated by the serum insulin area under the curve, was also higher in III/III infants [2417 (891-4041) pmol min/l vs. 1208 (592-2284) pmol min/l; P < 0.05]. Fasting and postload plasma glucose levels were similar in both groups. Analysis of covariance showed that genotype differences in fasting insulin sensitivity and insulin secretion were independent of size at birth...