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Hla And Type 1 Diabetes

Genetic Research Informs On Timing Of Type 1 Diabetes Development

Genetic Research Informs On Timing Of Type 1 Diabetes Development

Genetic Research Informs on Timing of Type 1 Diabetes Development LISBON, PORTUGAL New research may point to better ways of diagnosing type 1 diabetes in children and adults and predicting who will develop it in the future. Findings from two studies on the genetics of type 1 diabetes were presented recently at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting . In one study, information from the UK Biobank revealed differences in human leukocyte antigen (HLA) allele patterns between people who developed type 1 diabetes in adulthood a group that hasn't been genetically profiled before and those with childhood-onset type 1 diabetes. Those results were presented by Dr Nicholas JM Thomas of the Institute of Biomedical and Clinical Science, University of Exeter Medical School, United Kingdom. The latter follows Dr Thomas's startling UK Biobank data report at the 2016 EASD meeting that half of all type 1 formerly known as "juvenile" diabetes develops after 30 years of age. "In time, the hope is that we can develop an algorithm to help primary-care physicians to be able to stratify at diagnosis to get a clear idea of the likely type of diabetes," Dr Thomas told Medscape Medical News. In the other study, a previously derived genetic risk score developed by the scientists at University of Exeter that incorporates HLA and non-HLA T1D-associated single nucleotide polymorphisms (SNPs) was found to predict the risk of progression of islet autoimmunity and the development of type 1 diabetes among participants of the TrialNet Pathways to Prevention study. These individuals were positive for one or more type 1 diabetesassociated autoantibodies but did not have the condition at baseline. Those data were presented by Maria J Redondo, MD, PhD, of Baylor Colleg Continue reading >>

Human Leukocyte Antigen

Human Leukocyte Antigen

The human leukocyte antigen (HLA) system or complex is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans. These cell-surface proteins are responsible for the regulation of the immune system in humans. The HLA gene complex resides on a 3 Mbp stretch within chromosome 6p 21. HLA genes are highly polymorphic , which means that they have many different alleles , allowing them to fine-tune the adaptive immune system . The proteins encoded by certain genes are also known as antigens , as a result of their historic discovery as factors in organ transplants. Different classes have different functions: HLAs corresponding to MHC class I ( A , B , and C ) present peptides from inside the cell. For example, if the cell is infected by a virus, the HLA system brings fragments of the virus to the surface of the cell so that the cell can be destroyed by the immune system. These peptides are produced from digested proteins that are broken down in the proteasomes . In general, these particular peptides are small polymers , about 9 amino acids in length.[ citation needed ] Foreign antigens presented by MHC class I attract killer T-cells (also called CD8 positive- or cytotoxic T-cells) that destroy cells. MHC class I proteins associate with 2-microglobulin , which unlike the HLA proteins is encoded by a gene on chromosome 15 . HLAs corresponding to MHC class II ( DP , DM , DOA , DOB , DQ , and DR ) present antigens from outside of the cell to T-lymphocytes. These particular antigens stimulate the multiplication of T-helper cells (also called CD4 positive T cells), which in turn stimulate antibody -producing B-cells to produce antibodies to that specific antigen. Self-antigens are suppressed by regulatory T cells . HLAs corresponding to MHC class III enc Continue reading >>

Relationship Of Type 1 Diabetes With Human Leukocyte Antigen (hla) Class Ii Antigens Except For Dr3 And Dr4

Relationship Of Type 1 Diabetes With Human Leukocyte Antigen (hla) Class Ii Antigens Except For Dr3 And Dr4

Medicine Endocrinology and Metabolism "Type 1 Diabetes - Pathogenesis, Genetics and Immunotherapy" , book edited by David Wagner, ISBN 978-953-307-362-0, Published: November 25, 2011 under CC BY 3.0 license . The Author(s). Relationship of Type 1 Diabetes with Human Leukocyte Antigen (HLA) Class II Antigens Except for DR3 and DR4 4.3. DRB1*09:01-DQA1*03:02-DQB1*03:03 (DR9) haplotype Figure 1. Relationship between the frequency of the DR9 phenotype and the mean onset age. A significant positive correlation is observed between the frequency of the DR9 haplotype and the mean onset age (r2 = 0.742, P = 0.0274). DR9, DRB1*09:01-DQA1*03:02-DQB1*03:03. Relationship of Type 1 Diabetes with Human Leukocyte Antigen (HLA) Class II Antigens Except for DR3 and DR4 [1] Department of Endocrinology and Diabetes, Ichinomiya Municipal Hospital,, Japan Type 1 diabetes (T1D) is the form of the disease that occurs primarily as a result of -cell destruction. The American Diabetes Association (ADA) and the World Health Organization (WHO) have classified T1D into 2 categories, namely, immune-mediated (autoimmune) and idiopathic ( Alberti & Zimmet, 1998 ; Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997). In autoimmune T1D (type 1A diabetes), the rate of -cell destruction is quite variable, being rapid in some individuals and slow in others ( Zimmet et al., 1994 ). Markers of immune destruction, including islet cell autoantibodies (ICA), autoantibodies to insulin (IAA), autoantibodies to glutamic acid decarboxylase (GAD65), and autoantibodies to tyrosine phosphatases IA-2, are present in 8590% of individuals with T1D when fasting diabetic hyperglycemia is initially detected ( Verge et al., 1996 ). The rapid-onset (classic) form of T1D is commonly observed in chil Continue reading >>

Evaluation Of High-risk Type 1 Diabetes Hla-dr And Dq Haplotypes Using Three Single Nucleotide Polymorphisms In A Population From Southern Brazil

Evaluation Of High-risk Type 1 Diabetes Hla-dr And Dq Haplotypes Using Three Single Nucleotide Polymorphisms In A Population From Southern Brazil

Evaluation of high-risk type 1 diabetes HLA-DR and DQ haplotypes using three single nucleotide polymorphisms in a population from Southern Brazil GuilhermeCoutinhoKullmannDuarte 1 Email author , Human Leukocyte AntigenGenetic Risk FactorHuman Leukocyte Antigen TypeHaplotype CombinationAutoimmune Destruction Type 1 diabetes mellitus (T1D) accounts for ~10% of all diabetes cases, and it is caused by autoimmune destruction of pancreatic beta-cells, which leads to insulin deficiency and fates individuals to require insulin treatment to survive. The triggering of autoimmunity against beta-cells is caused by interaction between environmental and genetic risk factors. Among the several loci associated with T1D, the human leukocyte antigen (HLA) class II DR/DQ locus is the main genetic risk factor for T1D, accounting for 30-50% of genetic risk for this disease. Other genes have been associated with minor effects on T1D risk when compared with HLA, with different studies indicating that the effect of non-HLA polymorphisms on predisposition for T1D may be different according to HLA DR/DQ types. In this scenario, a recent study identified a minimum set of three polymorphisms (rs3104413, rs2854275, rs9273363) which can predict high-risk HLA-DR/DQ types relevant to T1D. To evaluate frequencies of high-risk T1D HLA-DR/DQ haplotypes in a Southern Brazilian population using a minimum set of HLA polymorphisms (rs3104413C/G, rs2854275A/C and rs9273363A/C). We analyzed 387 T1D patients (cases) and 375 healthy blood-donor subjects (controls). The local ethics committee approved the protocol, and all patients signed an informed consent form. Polymorphisms of interest were genotyped by allelic discrimination RT-PCR technique using TaqMan MGB probes (Life Technologies). Haplotype combination Continue reading >>

New Study Challenges Link Between Hla Class I Hyperexpression In Pancreas And Type 1 Diabetes

New Study Challenges Link Between Hla Class I Hyperexpression In Pancreas And Type 1 Diabetes

The cause of type 1 diabetes remains unknown. Several studies using immunohistochemistry (IHC) have independently reported hyperexpression of human leukocyte antigen (HLA) class I on pancreatic islet cells in young patients with recent-onset type 1 diabetes. Investigators have therefore suggested that HLA hyperexpression may be an important first step in the development of type 1 diabetes. However, a new study in The American Journal of Pathology challenges these findings and reports that results differ when quantitative molecular techniques are applied instead of IHC. The investigators suggest that the previously reported model may require reexamination. "IHC is the most commonly used method to display protein expression in tissues. However, the pattern of expression in composite tissues, such as the pancreas, should be interpreted with caution because obtained results critically depend on the accessibility of the epitope(s) recognized by the primary antibody. Availability of epitopes on proteins in tissue sections varies markedly between tissues, type of fixation, and staining technique," says Oskar Skog, PhD, of the Department of Immunology, Genetics, and Pathology of Uppsala University (Sweden). According to Dr. Skog and his co-investigators, the clinical manifestations of type 1 diabetes result from the loss of insulin-producing beta cells in the portion of the pancreas known as the endocrine (hormone-secreting) pancreas. However, the pancreas also contains exocrine tissue that produces digestive enzymes secreted into the small intestine. Researchers studied both endocrine and exocrine pancreatic tissue to see whether the findings were specific to the tissue directly affected by type 1 diabetes. The investigators, who are members of The Diabetes Virus Detection (Di Continue reading >>

The Type 1 Diabetes - Hla Susceptibility Interactome - Identification Of Hla Genotype-specific Disease Genes For Type 1 Diabetes

The Type 1 Diabetes - Hla Susceptibility Interactome - Identification Of Hla Genotype-specific Disease Genes For Type 1 Diabetes

The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes Affiliation: Hagedorn Research Institute and Steno Diabetes Center, Gentofte, Denmark Contributed equally to this work with: Caroline Brorsson, Niclas Tue Hansen Affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark Affiliation: Hagedorn Research Institute and Steno Diabetes Center, Gentofte, Denmark Affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark Affiliations: Hagedorn Research Institute and Steno Diabetes Center, Gentofte, Denmark, Department of Clinical Sciences, Lund University, Malm, Sweden, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark The individual contribution of genes in the HLA region to the risk of developing type 1 diabetes (T1D) is confounded by the high linkage disequilibrium (LD) in this region. Using a novel approach we have combined genetic association data with information on functional protein-protein interactions to elucidate risk independent of LD and to place the genetic association into a functional context. Genetic association data from 2300 single nucleotide polymorphisms (SNPs) in the HLA region was analysed in 2200 T1D family trios divided into six risk groups based on HLA-DRB1 genotypes. The best SNP signal in each gene was mapped to proteins in a human protein interaction network and their significance of clustering in functional network modules was evaluated. The significant network modules identified through this approach differed between the six HLA risk groups, which could be divided into two groups based on carrying the DRB1*0301 or the DRB1*0401 allele. Proteins identifi Continue reading >>

Original Article Non Hla Genetic Markers Association With Type-1 Diabetes Mellitus

Original Article Non Hla Genetic Markers Association With Type-1 Diabetes Mellitus

Abstract The currently available data identified IDDM1 and IDDM2 as 2 susceptibility loci for type 1 diabetes (T1D). The major histocompatibility complex (MHC)/HLA region referred to as IDDM1 contains several 100 genes known to have a great influence on T1D risk. Within IDDM2, a minisatellite variable number of tandem repeats (VNTR) locus in the insulin gene (INS) promoter region is likely to represent the etiologic polymorphism. The aim of the present work was to study the association between genotypes and susceptibility to T1D among Egyptian diabetic children and their family members. Twenty-five nuclear Egyptian families with 27 children having T1D, aged 3–14 years, their non-diabetic 44 sibs, aged 3–15 years and their parents were included in our study. All studied children were subjected to: detailed history and family pedigree. Thorough clinical examination and anthropometric measurements. Laboratory work up of diabetes including random blood sugar (RBS) and HbA1C. Molecular genetics of INS was studied in four steps; nucleic acid purification, amplification, sequencing and haplotyping using flanking single nucleotide polymorphisms (SNPs) as surrogate markers for minisatellite alleles identification. Analysis of variant repeat distribution among Egyptian families combined with flanking haplotypes revealed that all our diabetic children had class I alleles of INS; 9 had class IC+, 9 had class ID+ and 9 had class ID−, while all non-diabetic family members had class III alleles of INS. Therefore the three class I alleles were considered to be equally predisposing to T1D, while class III alleles are dominantly protective. There was significant positive correlations between body mass index (BMI) and both HbA1C and AST liver enzyme among diabetic children with clas Continue reading >>

Genetics Of The Hla Region In The Prediction Of Type 1 Diabetes

Genetics Of The Hla Region In The Prediction Of Type 1 Diabetes

Genetics of the HLA Region in the Prediction of Type 1 Diabetes Janelle A. Noble, Children's Hospital Oakland Research Institute, 5700 Martin Luther King, Jr. Way, Oakland, CA 94609, USA, [email protected] ; The publisher's final edited version of this article is available at Curr Diab Rep See other articles in PMC that cite the published article. Type 1 diabetes (T1D) is one of the most widely studied complex genetic disorders, and the genes in HLA are reported to account for approximately 40% to 50% of the familial aggregation of T1D. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The DR-DQ haplotypes conferring the highest risk are DRB1*03:01-DQA1*05:01-DQB1*02:01 (abbreviated DR3) and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02; abbreviated DR4). The risk is much higher for the heterozygote formed by these two haplotypes (OR = 16.59; 95% CI, 13.720.1) than for either of the homozygotes (DR3/DR3, OR = 6.32; 95% CI, 5.127.80; DR4/DR4, OR = 5.68; 95% CI, 3.91). In addition, some haplotypes confer strong protection from disease, such as DRB1*15:01-DQA1*01:02-DQB1*06:02 (abbreviated DR2; OR = 0.03; 95% CI, 0.010.07). After adjusting for the genetic correlation with DR and DQ, significant associations can be seen for HLA class II DPB1 alleles, in particular, DPB1*04:02, DPB1*03:01, and DPB1*02:02. Outside of the class II region, the strongest susceptibility is conferred by allele B*39:06 (OR =10.31; 95% CI, 4.2125.1) and other HLA-B alleles. In addition, several loci in the class III region are reported to be associated with T1D, as are some loci telomeric to class I. Not surprisingly, current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ Continue reading >>

Genetics Of Type 1 Diabetes

Genetics Of Type 1 Diabetes

In western populations, each child has a 0.3–0.4% risk of developing diabetes by the age of 20 years; the risk increases 15-fold in siblings of an affected child. Lifetime risks are more difficult to estimate, but may be about twice as high as this. Some 50% of the genetic risk of type 1 diabetes is conferred by genes in the human leucocyte antigen (HLA) region on chromosome 6. The HLA Class II susceptibility haplotypes DR4-DQ8 and DR3-DQ2 are present in 90% of children with type 1 diabetes, whereas DR15-DQ6 is associated with protection. High risk HLA haplotypes in a child with no family history of disease confer a risk similar to that of having an affected sibling (5–6%), and this risk rises rapidly if one or both haplotypes are shared with the affected sibling. The promoter region of the insulin gene on chromosome 11 contributes about 10% of genetic susceptibility. Many other genes (currently more than 40) make a minor contribution to type 1 diabetes, and several are of particular interest because they influence different aspects of immune function. Their ability to predict diabetes is, however, limited. Empirical risks By the age of 20 years, type 1 diabetes will have affected some 0.3–0.4% of children in the background population in western countries, and about 6% of siblings of childhood onset cases, giving a ratio (λs) of 15. Early-onset diabetes carries a higher familial risk, and affected fathers are more likely to transmit type 1 diabetes to their offspring than affected mothers, with risks being 6–9% and 1–3%, respectively.[1] These estimates represent the risk of diabetes development by young adult life, not the lifetime risk. The latter is not well established, and may be as high as 1% in the background population and 15% in siblings. Siblings wh Continue reading >>

Hla Genetic Discrepancy Between Latent Autoimmune Diabetes In Adults And Type 1 Diabetes: Lada China Study No. 6

Hla Genetic Discrepancy Between Latent Autoimmune Diabetes In Adults And Type 1 Diabetes: Lada China Study No. 6

The discrepancies in terms of human leukocyte antigen (HLA)-DRB1-DQA1-DQB1 conferred risks between latent autoimmune diabetes in adults (LADA) and type 1 diabetes (T1D) patients remained almost completely unknown. The goal of the current study is to determine and compare HLA-conferred risks between LADA and T1D. A case-control study was conducted in a representative Chinese data set containing 520 T1D patients, 562 LADA patients, and 1065 controls. The frequencies and odds ratios for HLA susceptible haplotypes and genotypes and for arginine at residue 52 in the DQ- chain or aspartic acid at residue 57 in the DQ- chain were analyzed. DRB1*0405-DQA1*03-DQB1*0401 and DRB1*0901-DQA1*03-DQB1*0303 are the major LADA susceptible haplotypes, which also confer comparable risks for T1D (odds ratio 2.02 vs 2.20 and 1.61 vs 2.30, respectively). The strongly associated T1D haplotype DRB1*0301-DQA1*05-DQB1*0201 is also associated with LADA but confers only half of the T1D risk (odds ratio 2.65 vs 4.84). Interestingly, the most susceptible T1D haplotypes, DRB1*0901-DQA1*05-DQB1*0201, DRB1*0301-DQA1*03-DQB1*0201, and DRB1*0301-DQA1*03-DQB1*0303, are not associated with LADA. Genotypes for DR3/DR3, DR3/DR9, and DR9/DR9 are highly associated with T1D susceptibility, whereas only DR9/DR9 confers risk for LADA. DR3/DR3 is the high-risk genotype in Chinese T1D patients, which manifests similar risk as the DR3/DR4 genotype in Caucasians but with a lower frequency. DR9/DR9 is the high risk LADA genotype in Chinese. Alleles with DQ- arginine at residue 52-positive, DQ- aspartic acid at residue 57-negative, and their combination formed in cis or trans confer susceptibility to T1D but not to LADA. Our results suggest that LADA risk conferred by HLA-DRB1-DQA1-DQB1 loci in Chinese differs signifi Continue reading >>

Islet Cell Hyperexpression Of Hla Class I Antigens: A Defining Feature In Type 1 Diabetes

Islet Cell Hyperexpression Of Hla Class I Antigens: A Defining Feature In Type 1 Diabetes

, Volume 59, Issue11 , pp 24482458 | Cite as Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes Human pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear. One potentially contributing factor is hyperexpression of HLA class I antigens. This was first described approximately 30years ago, but has never been fully characterised and was recently challenged as artefactual. Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes. The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it. Pancreas samples from type 1 diabetes patients with residual insulin-containing islets (n = 26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD domain containing 5 (NLRC5) and islet hormones. RNA was extracted from islets isolated by laser-capture microdissection from nPOD and DiViD samples and analysed using gene-expression arrays. Hyperexpression of HLA class I was observed in the insulin-containing islets of type 1 diabetes patients from all three tissue collections, and was confirmed at both the RNA and protein levels. The expression of 2-microglobulin (a second component required for the generation of functional HLA class I complexes) was also elevated. Both classical HLA class I isoforms (i.e. HLA-ABC) as well as a non-classical HLA molecule, HLA-F, were hyperexpressed in insulin-containing islets. Continue reading >>

Hla Class Ii Allele, Haplotype, And Genotype Associations With Type 1 Diabetes In Benin: A Pilot Study

Hla Class Ii Allele, Haplotype, And Genotype Associations With Type 1 Diabetes In Benin: A Pilot Study

HLA Class II Allele, Haplotype, and Genotype Associations with Type 1 Diabetes in Benin: A Pilot Study 1UFR de Biologie Humaine, Facult des Sciences de la Sant, Universit dAbomey-Calavi, Cotonou, Benin 2Laboratoire de Recherche en Biologie Applique, Ecole Polytechnique d'Abomey-Calavi, Universit dAbomey-Calavi, Abomey-Calavi, Benin 3Laboratoire de Biologie et de Typage Molculaire en Microbiologie, Universit dAbomey-Calavi, Abomey-Calavi, Benin Correspondence should be addressed to Kaossarath A. Fagbemi Received 28 February 2017; Revised 30 May 2017; Accepted 5 July 2017; Published 20 July 2017 Copyright 2017 Kaossarath A. Fagbemi et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Several studies have reported the implication of HLA-DR/DQ loci in the susceptibility to type 1 diabetes (T1D). Since no such study has yet been performed in Benin, this pilot one aimed at assessing HLA class II allele, haplotype, and genotype associations with T1D. Material and Methods. Class II HLA genotyping was performed in 51 patients with T1D and 51 healthy unrelated controls by means of the PCR-SSP method. The diagnosis of T1D was set up according to American Diabetes Association criteria. Odds ratio (OR) and its 95% confidence interval (95% CI) were calculated to assess the associations between T1D and HLA alleles, haplotypes, and genotypes. Results. Participants were aged 124 years. T1D was significantly associated with DR3, DQA1 02:01, and DR3-DR4. No significant associations were observed with DR4, DQB1 06:02. Conclusion. Certain HLA class II alleles, haplotypes, and genotypes were related to T1D and m Continue reading >>

Genetics Of Type 1 Diabetes

Genetics Of Type 1 Diabetes

The HLA region maps to chromosome 6p21.31. The classical HLA loci are encoded in a region of DNA approximately 4 Mb, with the class II loci at the centromeric end of the region and the class I loci at the telomeric end. The region contains >200 identified genes, over half of which are predicted to be expressed. A schematic representation of the HLA region, with T1D-relevant genes indicated, is shown in Figure 1. Only some of the HLA region genes are involved in the immune response; in particular, the genes that encode the classical HLA class I (A, B, and C) and class II (DR, DQ, and DP) antigens. Genes encoding classical HLA class I and class II antigens flank a chromosomal region that is sometimes referred to as the “class III region,” which contains some immunologically relevant genes (e.g., tumor necrosis factor [TNFA]) but no classical HLA genes. Products of loci encoding the six classical class I (A, B, and C) and class II (DR, DQ, and DP) antigens are structurally similar, cell-surface proteins that bind antigenic peptides and present them to T cells. DR-encoding genes differ from those encoding DQ and DP in two important ways. First, the DRA1 gene, which encodes the α chain of the DR molecule, is essentially monomorphic and does not require genotyping. Second, the DRB1 gene is present on all chromosomes, but additional DRB genes are present on specific haplotypes. Some of the additional DRB genes, e.g., DRB2, are pseudogenes; however, three of these (DRB3, DRB4, and DRB5) encode functional polypeptide chains that can pair with the DRA1 gene product to create a functional antigen. The role of these additional DR antigens in disease susceptibility is not yet understood. Molecules resembling the classical class I antigens are encoded in the HLA region, includin Continue reading >>

Genetics Of The Hla Region In The Prediction Of Type 1 Diabetes.

Genetics Of The Hla Region In The Prediction Of Type 1 Diabetes.

Curr Diab Rep. 2011 Dec;11(6):533-42. doi: 10.1007/s11892-011-0223-x. Genetics of the HLA region in the prediction of type 1 diabetes. Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA. [email protected] Type 1 diabetes (T1D) is one of the most widely studied complex genetic disorders, and the genes in HLA are reported to account for approximately 40-50% of the familial aggregation of T1D. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The DR-DQ haplotypes conferring the highest risk are DRB1*03:01-DQA1*05:01-DQB1*02:01 (abbreviated "DR3") and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02; abbreviated "DR4"). The risk is much higher for the heterozygote formed by these two haplotypes (OR = 16.59; 95% CI, 13.7-20.1) than for either of the homozygotes (DR3/DR3, OR = 6.32; 95% CI, 5.12-7.80; DR4/DR4, OR = 5.68; 95% CI, 3.91). In addition, some haplotypes confer strong protection from disease, such as DRB1*15:01-DQA1*01:02-DQB1*06:02 (abbreviated "DR2"; OR = 0.03; 95% CI, 0.01-0.07). After adjusting for the genetic correlation with DR and DQ, significant associations can be seen for HLA class II DPB1 alleles, in particular, DPB1*04:02, DPB1*03:01, and DPB1*02:02. Outside of the class II region, the strongest susceptibility is conferred by class I allele B*39:06 (OR =10.31; 95% CI, 4.21-25.1) and other HLA-B alleles. In addition, several loci in the class III region are reported to be associated with T1D, as are some loci telomeric to class I. Not surprisingly, current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ loci, which is then combined with family history and screening for autoantibodies directed against islet-cell a Continue reading >>

Hla Class I And Genetic Susceptibility To Type 1 Diabetes

Hla Class I And Genetic Susceptibility To Type 1 Diabetes

HLA Class I and Genetic Susceptibility to Type 1 Diabetes Results From the Type 1 Diabetes Genetics Consortium 1Children's Hospital Oakland Research Institute, Oakland, California; 5Roche Molecular Systems, Pleasanton, California; 1Children's Hospital Oakland Research Institute, Oakland, California; 2Department of Twin Research and Genetic Epidemiology, King's College London, London, U.K.; 3Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia; 4Clinical Chemistry, University Hospital, Malm, Sweden; 5Roche Molecular Systems, Pleasanton, California; 6Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia. Corresponding author: Janelle A. Noble, [email protected] . Received 2010 May 15; Accepted 2010 Aug 13. Copyright 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details. This article has been cited by other articles in PMC. We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study. Complete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients. Significant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetesassociated Continue reading >>

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