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Type 1 Diabetes Hla-dr3

Definition Of High-risk Type 1 Diabetes Hla-dr And Hla-dq Types Using Only Three Single Nucleotide Polymorphisms

Definition Of High-risk Type 1 Diabetes Hla-dr And Hla-dq Types Using Only Three Single Nucleotide Polymorphisms

Definition of High-Risk Type 1 Diabetes HLA-DR and HLA-DQ Types Using Only Three Single Nucleotide Polymorphisms 1Centre for Diabetes Research, The Western Australian Institute for Medical Research, Perth, Western Australia, Australia 2Centre for Medical Research, University of Western Australia, Perth, Western Australia, Australia 1Centre for Diabetes Research, The Western Australian Institute for Medical Research, Perth, Western Australia, Australia 2Centre for Medical Research, University of Western Australia, Perth, Western Australia, Australia 1Centre for Diabetes Research, The Western Australian Institute for Medical Research, Perth, Western Australia, Australia 2Centre for Medical Research, University of Western Australia, Perth, Western Australia, Australia 3Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Victoria, Australia 4Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Corresponding author: Grant Morahan, [email protected] . Received 2012 Oct 9; Accepted 2013 Jan 21. Copyright 2013 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. Evaluating risk of developing type 1 diabetes (T1D) depends on determining an individuals HLA type, especially of the HLA DRB1 and DQB1 alleles. Individuals positive for HLA-DRB1*03 (DR3) or HLA-DRB1*04 (DR4) with DQB1*03:02 (DQ8) have the highest risk of developing T1D. Currently, HLA typing methods are relatively expensive and time consuming. We sought to determine the minimum number of single nucleotide polymorphisms (SNPs) that could rapidly 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 >>

Hla Dr3-dq2 - An Overview | Sciencedirect Topics

Hla Dr3-dq2 - An Overview | Sciencedirect Topics

Veena Taneja, ... Chella S. David, in The Autoimmune Diseases (Fifth Edition) , 2014 Type 1 diabetes shows familial clustering and is linked to the presence of HLA-DQ8/DR4 and HLA-DQ2/DR3 haplotypes. Within the HLA-DQ8/DR4 haplotype, HLA-DQ8 is believed to be the predisposing class II molecule. Most knowledge about autoimmune diabetes comes from a special strain of NOD mice which develop spontaneous diabetes. Elegant genetic studies performed in these mice have mapped the development of disease to the presence of MHC class II molecule H2-Ag7. Interestingly, the H2-Ag7 molecule shows strong structural and functional homology with the human HLA-DQ8 molecule, thus strengthening the major pathogenic role of DQ8 in human T1D. Although HLA-DQ8 transgenic mice do not develop spontaneous diabetes, they lost tolerance to self-GAD65 antigen, leading to activation of autoreactive T cells in the periphery and pancreas. These transgenic mice show insulitis but do not progress to diabetes. As with DQ8 transgenic mice, the presence of a T1D predisposing MHC allele in certain individuals could result in the escape of autoreactive T cells against pancreatic antigens. However, the onset of disease might require a second hit in the pancreas. This second hit can come in the form of virus/bacterial infection, and/or overproduction of a cytokine, overexpression of an accessory molecule or other genetically-determined variations completing the causal pie and precipitation of disease in these individuals. To simulate such an insult in the pancreas, we generated HLA-DQ8 (disease-susceptible) and HLA-DQ6 (disease-resistant) transgenic mice expressing the costimulatory molecule CD80 (B7.1) in islet cells under the rat insulin promoter (RIP) (Wen et al., 2000). HLA-DQ8/RIP/B7.1 mice developed spo Continue reading >>

Excess Of Dr3/4 In Type I Diabetes. What Does It Portend?

Excess Of Dr3/4 In Type I Diabetes. What Does It Portend?

Excess of DR3/4 in type I diabetes. What does it portend? Rubinstein P, Walker M, Ginsberg-Fellner F. The HLA-DR genotypes of 158 new type I diabetic probands from simplex familiesare compared with those of 43 multiply affected sibships. There were nosignificant differences in the gene frequencies of the insulin-dependent diabetesmellitus (IDDM)-associated alleles, DR3 and DR4, and whereas the DR3/4heterozygotes were as frequent among simplex probands as among the first affectedof multiplex sibships, subsequently affected sibs displayed lower frequencies of this genotype in this as well as in previously reported samples, indicating that the excessive risk associated with DR3/4 heterozygosity depends on the order ofaffection and thus on environmental factors. It is proposed that the penetranceof the susceptibility gene is enhanced by epistatic effects of this genotype and that this enhancement is strongest under conditions of low environmentalliability. Thus, the excessive risk for DR3/4 individuals appears to depend onsecondary interactions between DR and the environmental factors that trigger the onset of this disease and does not in itself indicate the existence of distinctsusceptibility alleles in coupling with these genes, i.e., of geneticheterogeneity or overdominance. Continue reading >>

Type 1 Diabetes In The Spanish Population: Additional Factors To Class Ii Hla-dr3 And -dr4

Type 1 Diabetes In The Spanish Population: Additional Factors To Class Ii Hla-dr3 And -dr4

Type 1 Diabetes in the Spanish Population: additional factors to Class II HLA-DR3 and -DR4 Urcelay et al; licensee BioMed Central Ltd.2005 The Major Histocompatibility Complex is the main genetic contributor to susceptibility to type 1 diabetes (T1D); genome-wide scans have consistently mapped increased predisposition to this region. The highest disease risk has been associated with HLA-DR3 and HLA-DR4. In particular, the DR3-positive ancestral haplotype 18.2 was reported as highly diabetogenic. We aimed to corroborate whether this haplotype increases the susceptibility conferred by the DQ2-DR3 alleles in a Mediterranean population. We also searched for additional susceptibility factors to the classic DQ2-DR3 and DQ8-DR4. Genetic MHC markers were analysed in a case-control study with 302 T1D patients and 529 ethnically matched controls. DR3-TNFa1b5 carrier rate was significantly higher in DR3-positive heterozygous T1D patients than in DR3-positive heterozygous controls (p = 0.0019; odds ratio OR [95% confidence interval CI] = 2.26 [1.33.93]). This data was confirmed analysing the allelic frequency, which includes the information corresponding to the DR3-homozygous individuals (p = 0.001; OR = 2.09) and by using the Arlequin software to check the DR3-positive haplotypes (p = 0.004;OR = 1.93). The present results provide strong evidence of a second susceptibility region in the ancestral haplotype 18.2 in the Spanish population. Moreover, we searched for T1D susceptibility factors in addition to the MHC classical ones, within the DR2-DQ6/DR3-DQ2/DR4-DQ8 negative population. Several genetic markers in both MHC class II (DQA1*0101-DQB1*0501 [p = 0.007;OR = 2.81], DQA1*0201-DQB1*0202 [p = 0.03; OR = 2.35]) and III (TNFa2b1 [p = 0.01 OR = 2.74], BAT-2*2 [p = 0.004; OR = 3.19] Continue reading >>

Modulation Of Insulitis And Type 1 Diabetes By Transgenic Hla-dr3 And Dq8 In Nod Mice Lacking Endogenous Mhc Class Ii.

Modulation Of Insulitis And Type 1 Diabetes By Transgenic Hla-dr3 And Dq8 In Nod Mice Lacking Endogenous Mhc Class Ii.

To evaluate the contributions of DR3 and DQ8 to the etiopathogenesis of type 1 diabetes in a diabetes-predisposing milieu, we developed human leukocyte antigen (HLA) transgenic mice on the nonobese diabetic (NOD) background in the absence of the endogenous class II molecule, I-A(g7) and studied the incidence of both spontaneous and experimental (induced) autoimmune diabetes. Transgenic expression of HLA-DR3 and -DQ8 (either alone or in combination) did not confer susceptibility to spontaneous or cyclophosphamide-induced type 1 diabetes. Expression of I-A(g7) was mandatory for development of spontaneous or cyclophosphamide-induced diabetes. However, multiple low doses of streptozotocin could induce diabetes in all groups of mice independent of the class II molecules expressed. In unmanipulated mice, only islets from I-A(g7+/+) mice revealed significant intra-islet infiltration. Although a characteristic peri-insulitis/peri-ductulitis was present in Abeta(0)/NOD mice, islets from DR3, DQ8 and DR3 x DQ8 double transgenic mice demonstrated significantly less infiltration. In conclusion, transgenic expression of HLA-DR3 and -DQ8 associated with predisposition to type 1 diabetes alone is not sufficient to induce spontaneous diabetes in NOD mice lacking endogenous class II molecules. Continue reading >>

Association Of Major Histocompatibility Complex Class 1 Chain-related Gene A Dimorphism With Type 1 Diabetes And Latent Autoimmune Diabetes In Adults In The Algerian Population

Association Of Major Histocompatibility Complex Class 1 Chain-related Gene A Dimorphism With Type 1 Diabetes And Latent Autoimmune Diabetes In Adults In The Algerian Population

Major histocompatibility complex class I chain-related gene A (MICA-129) dimorphism was investigated in 73 autoimmune diabetes patients (type 1 diabetes and latent autoimmune diabetes in adults) and 75 controls from Algeria. Only MICA-129 Val allele and MICA-129 Val/Val genotype frequencies were higher among patients than in the control group. Statistical analysis of the estimated extended HLA-DR-DQ-MICA haplotypes shown that individual effects of MICA alleles on HLA-DQ2-DR3-MICA-129 Val/Val and HLA-DQ8-DR4-MICA-129 Val/Val haplotypes were significantly higher in patients than in the control groups. These preliminary data might suggest a relevant role of MICA-129 Val/Val single nucleotide polymorphism (weak/weak binders of NKG2D receptor) in the pathogenesis of T1D and LADA. Type 1 diabetes (T1D) is a typical autoimmune disease that results from the destruction of insulin-producing cells of the pancreas; the disease was once thought to be mediated exclusively by CD4+ T cells and is now recognized as one in which autoreactive CD8+ T cells play a fundamental pathogenic role ( 37 ). The etiology of T1D is complex and involves both genetic and environmental factors which play important roles ( 7 , 11 , 12 ). A permissive genetic background is required for the development of the islet autoimmune process generating antibodies (Ab) against insulin (IAA), glutamic acid decarboxylase isoform 65 (GADA65-Ab), and protein tyrosine phosphatase (IA2) ( 6 , 39 ). In 1986, Groop et al. showed that islet cell antibodies identify latent type 1 diabetes mellitus (T1DM) in patients aged 35 to 75 years at diagnosis ( 20 ). These subclasses of diabetes have been referred to as latent autoimmune diabetes in adults (LADA). Autoantibodies to glutamate decarboxylase (GAD65Ab) are the most sensi Continue reading >>

Hla-dr3 - Wikipedia

Hla-dr3 - Wikipedia

major histocompatibility complex, class II, DR3 HLA-DR3 is composed of the HLA-DR17 and HLA-DR18 split 'antigens' serotypes. DR3 is a component gene-allele of the AH8.1 haplotype in Northern and Western Europeans. Genes between B8 and DR3 on this haplotype are frequently associated with autoimmune disease. Type 1 diabetes mellitus is strongly associated with HLA-DR3 or HLA-DR4. DR17 and DR3 recognition of some DRB1*03 alleles [1] Some DR3 also react with HLA-DR17 and/or HLA-DR18 . The DRB1*0304 primarily reacts with DR3. The serotypes of *0305, *0306, *0308 to *0331 are unknown. DR3 and/or DQ2 is associated with Moreen's ulceration, [7] "bout onset" multiple sclerosis, [8] Grave's disease [9] and systemic lupus erythematosus [10] DR3-DQ2 linkage is associated with coeliac disease , dermatitis herpetiformis , Diabetes mellitus type 1 . DR3-DR2 is the serological marker for HLA-DQ2.5cis isoform. Although it cannot identify the alpha ".5" chain of HLA DQ, DQA1*0501 gene is almost always found within the DR3-DQ2 haplotype Eurasia (however is older studies DQA1*0505 is commonly confused with DQA1*0501) Wiencke K, Karlsen TH, Boberg KM, et al. (2007). "Primary sclerosing cholangitis is associated with extended HLA-DR3 and HLA-DR6 haplotypes". Tissue Antigens. 69 (2): 1619. doi : 10.1111/j.1399-0039.2006.00738.x . PMID 17257319 . Pollack MS, Gold J, Metroka CE, Safai B, Dupont B (1984). "HLA-A,B,C and DR antigen frequencies in acquired immunodeficiency syndrome (AIDS) patients with opportunistic infections". Hum. Immunol. 11 (2): 99103. doi : 10.1016/0198-8859(84)90048-X . PMID 6333416 . Mann DL, Murray C, O'Donnell M, Blattner WA, Goedert JJ (1990). "HLA antigen frequencies in HIV-1-related Kaposi's sarcoma". J. Acquir. Immune Defic. Syndr. 3 Suppl 1: S515. PMID 2395088 . We Continue reading >>

Genetics Of Type 1 Diabetes

Genetics Of Type 1 Diabetes

Abstract BACKGROUND: Type 1 diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic β cells. The major susceptibility locus maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene markers have been confirmed. CONTENT: Although HLA class II alleles account for up to 30%–50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk with smaller effects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and other recently discovered loci. Genomewide association studies performed with high-density single-nucleotide–polymorphism genotyping platforms have provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remain to be performed. Children born with the high-risk genotype HLADR3/4-DQ8 comprise almost 50% of children who develop antiislet autoimmunity by the age of 5 years. Genetic risk for type 1 diabetes can be further stratified by selection of children with susceptible genotypes at other diabetes genes, by selection of children with a multiple family history of diabetes, and/or by selection of relatives that are HLA identical to the proband. SUMMARY: Children with the HLA-risk genotypes DR3/4-DQ8 or DR4/DR4 who have a family history of type 1 diabetes have more than a 1 in 5 risk for developing islet autoantibodies during childhood, and children with the same HLA-risk genotype but no family history have approximately a 1 in 20 risk. Determining extreme genetic risk is a prerequisite for the implementation of primary prevention trials, which are now underway for relatives of individuals with type 1 diabetes. Type 1 diabetes (T1D),2 a multifactorial disease with a strong genetic compone Continue reading >>

Journal Of Autoimmunity 27 (2006) 174e181 Www.elsevier.com/locate/issn/08968411

Journal Of Autoimmunity 27 (2006) 174e181 Www.elsevier.com/locate/issn/08968411

A genetic explanation for the rising incidence of type 1 diabetes, a polygenic disease Z.L. Awdeh a,h,*, Edmond J. Yunis a,b,e, Mark J. Audeh f, Dolores Fici a,h, Alberto Pugliese g, Charles E. Larsen a,c, Chester A. Alper a,d a The CBR Institute for Biomedical Research, 800 Huntington Avenue, Boston, MA 02115, USA b Department of Pathology, Harvard Medical School, Boston, MA 02115, USA c Department of Medicine, Harvard Medical School, Boston, MA 02115, USA d Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA e Dana-Farber Cancer Institute, Boston, MA 02115, USA f Boston College, Chestnut Hill, MA 02467, USA g Diabetes Research Institute, University of Miami School of Medicine, Miami, FL 33101, USA h Pulsar Clinical Technologies Inc., 767 Concord Avenue, Cambridge, MA 02138, USA Abstract We had earlier hypothesized, if parents originated from previously isolated populations that had selected against different critical suscepti- bility genes for a polygenic disease, their offspring could have a greater risk of that disease than either parent. We therefore studied parents of patients with type 1 diabetes (T1D). We found that parents who transmitted HLA-DR3 to HLA-DR3/DR4 patients had different HLA-A allele frequencies on the non-transmitted HLA haplotype than HLA-DR4-transmitters. HLA-DR3-positive parents also had different insulin (INS ) gene allele frequencies than HLA-DR4-positive parents. Parent pairs of patients had greater self-reported ethnicity disparity than parent pairs in control families. Although there was an excess of HLA-DR3/DR4 heterozygotes among type 1 diabetes patients, there were significantly fewer HLA-DR3/DR4 heterozygous parents of patients than expected. These findings are consistent with HLA-DR and INS VNTR alleles mark- ing b Continue reading >>

Risk For Cardiovascular Autonomic Neuropathy Is Associated With The Hla-dr3/4 Phenotype In Type I Diabetes Mellitus

Risk For Cardiovascular Autonomic Neuropathy Is Associated With The Hla-dr3/4 Phenotype In Type I Diabetes Mellitus

Risk for Cardiovascular Autonomic Neuropathy Is Associated with the HLA-DR3/4 Phenotype in Type I Diabetes Mellitus Joshua Barzilay, MD; James H. Warram, MD, SCD; Lawrence I. Rand, MD; Michael A. Pfeifer, MD; Andrzej S. Krolewski, MD, PhD Objective: To identify risk factors for the development of cardiovascular autonomic neuropathy in patients with juvenile-onset type I diabetes mellitus. Design: Cross-sectional examination of an inception cohort 15 to 21 years after the onset of diabetes. Patients: Seventy-nine patients with type I diabetes who experienced onset of disease before 21 years of age and who were followed for 15 to 21 years. Measurements: Autonomic nerve function was evaluated in all patients using deep breathing and tilt tests. On the basis of these tests, an index of cardiovascular autonomic neuropathy was derived and patients were classified as having intact, mildly impaired, or significantly impaired autonomic function. Results: The group with significantly impaired function had a higher mean hemoglobin A1 at the time of examination than the group without impairment, yet the groups did not differ regarding glycemie control during the first decade of diabetes. The HLA-DR3/4 phenotype was present in more than 50% of the patients with significant autonomic dysfunction and conferred relative odds of 6.2 (95% Cl, 1.7 to 23.3) for the development of autonomic neuropathy when compared with other HLA-DR phenotypes. Sex, percent ideal body weight, and smoking did not have a statistically significant effect on the development of autonomic neuropathy. Conclusions: The development of cardiovascular autonomic neuropathy in type I diabetes mellitus is strongly associated with the HLA-DR3/4 phenotype. Thus, genetic predisposition may play an important role in the dev Continue reading >>

The Frequency Of Hla Drb1-dqb1 Alleles In Autoimmune Type 1 Diabetes With Or Without Autoimmune Thyroid Disease El-ahwal L, Abdel-bar Es - Tanta Med J

The Frequency Of Hla Drb1-dqb1 Alleles In Autoimmune Type 1 Diabetes With Or Without Autoimmune Thyroid Disease El-ahwal L, Abdel-bar Es - Tanta Med J

A common genetic susceptibility has long been reported between type 1 diabetes (T1D) and autoimmune thyroid disease (AITD). The HLA region became the first candidate to be studied for this association. The aim of this study was to identify the frequency of HLA DRB1-DQB1 alleles in T1D with or without AITD to clarify the susceptibility and the resistance of the two diseases. The study included 75 unrelated patients with T1D. About 50 T1D patients had no AITD (30 male and 20 female), 25 T1D patients had AITD (eight male and 17 female), and 40 healthy individuals served as the control group (17 male and 23 female) with mean ages of 40.6 2.0, 40.5 3.9, and 39 4.3 years, respectively. The following investigations were performed on all participants: the thyroid profile (free T4, FT3, and thyroid-stimulating hormone), thyroid peroxidase antibodies (anti-TPO), and thyroglobulin antibodies (anti-TG). Autoantibodies against glutamic acid decarboxylase (anti-GAD) were determined. HLA-DRB1 and HLA-DQB1 alleles were determined by PCR-SSOP methods. HLA class II alleles showed an increased frequency of DRB1*0101, DRB1*0301, DRB1*0402, DRB1*0403, and total DR*04 alleles with DQB1*0201 and DQB1*0302 alleles both in T1D patients with AITD and in T1D patients without AITD in comparison with the control group. The frequency of the DRB1*0401 allele was significantly higher only in T1D patients without AITD in comparison with the control group. The frequency of the DQB1*0301 allele was significantly higher only in T1D patients with AITD in comparison with the control group. However, frequencies of DRB1*1001, DRB1*1101, and DRB1*1501 with DQB1*0404, DQB1*0601, DQB1*0602, and DQB1*0603 alleles were significantly lower both in T1D patients with AITD and in T1D patients without AITD in comparis Continue reading >>

Hla-dr3 - An Overview | Sciencedirect Topics

Hla-dr3 - An Overview | Sciencedirect Topics

Albert J. Czaja MD, in GI/Liver Secrets (Fourth Edition) , 2010 Do the HLA phenotypes influence disease expression and outcome? Yes. Both HLA DR3 and HLA DR4 and the associated alleles, DRB1*0301 and DRB1*0401, have been associated with different clinical manifestations and outcomes in white North American and northern European patients (Table 18-7). Individuals with HLA DR3 (DRB1*0301) develop their disease at an early age, and they have more active disease, as assessed by serum aminotransferase levels and histologic features, than patients with other HLA. They also relapse more frequently after corticosteroid withdrawal, enter remission less commonly, deteriorate more often, and require liver transplantation more frequently. In contrast, patients with HLA DR4 (DRB1*0401) are older and more commonly women than patients with HLA DR3 (DRB1*0301). They have higher serum levels of gamma globulin, a greater frequency of concurrent immunologic diseases, and a greater likelihood of entering remission during therapy. Ankylosing spondylitisHLA-B27 (B-2701, B-2704, B-2705); Diabetes mellitus type 1HLA-DR3 and -DR4, and HLA-B (B-39, B-18) and HLA-A (A-24); Graves diseaseHLA-DR3 (DRB1-08), HLA-C (C-07), and HLA-B8 (B-08); Hashimotos thyroiditisHLA-DR4 (and -DR3); Multiple sclerosisHLA-DR15, HLA-C (C-05, and C-15); Rheumatoid arthritisHLA-alleles as follows: DRB1-0101, -0102, -0401, -0404, -0405, -0408, -1001, -1402); Systemic lupus erythematosusHLA-DR3, -DR8, and -DR15. Kareem Sassi, ... Sammy Saab, in Transplantation of the Liver (Third Edition) , 2015 Recurrence of AIH was found to be more commonly associated with HLA-DR3 or HLA-DR4positive recipients regardless of donor status, but these findings have not been universally confirmed.10,11,101 There was no increased risk dependi 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 >>

Type 1 Diabetes Risk For Hla-dr3 Haplotypes Depends On Genotypic Context: Association Of Dpb1 And Hla Class I Loci Among Dr3 And Dr4 Matched Italian Patients And Controls

Type 1 Diabetes Risk For Hla-dr3 Haplotypes Depends On Genotypic Context: Association Of Dpb1 And Hla Class I Loci Among Dr3 And Dr4 Matched Italian Patients And Controls

Type 1 diabetes risk for HLA-DR3 haplotypes depends on genotypic context: Association of DPB1 and HLA class I loci among DR3 and DR4 matched Italian patients and controls 1Childrens Hospital Oakland Research Institute, Oakland, CA 2Department of Clinical Sciences, Sapienza University, Rome, Italy 3Department of Paediatrics, IRCCS G. Gaslini Institute, University of Genova, Italy 4Campus Bio Medico University, Rome, Italy Corresponding author: Janelle A. Noble, Ph.D., Childrens Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, 510-450-7657 (voice), 510-450-7910 (fax), E-mail: [email protected] The publisher's final edited version of this article is available at Hum Immunol See other articles in PMC that cite the published article. Patients with high-risk HLA-DR-DQ genotypes for type 1 diabetes (T1D) were compared to HLA-matched controls to evaluate T1D risk for other HLA loci, including HLA-A, -B, -Cw, and DPB1. Patients (n=133) with high-risk genotypes (DR3/DR3, DR3/DR4, DR4/DR4) were selected from the Lazio (Rome) region of Italy. Screening of more than 9000 subjects from the Lazio region and northern Italy yielded 162 controls with high- T1D-risk haplotypes. Although the overall distributions were not significantly different, allele frequency differences were discovered between the controls from Lazio and those from Northern Italy for some alleles previously shown to affect T1D risk, such as A*3002, DPB1*0301, and DPB1*0402. Therefore, Lazio patient data were compared both to the Lazio subset of controls (n=53) and to the entire group of controls for association analyses. Significant allele frequency differences between patients and DR-DQ-matched controls were found for specific alleles at all loci. Data for the DR3/DR3 subset of Continue reading >>

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