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Genetic Basis Of Type 1 Diabetes

Genetics Of Type 1 Diabetes

Genetics Of Type 1 Diabetes

1. Introduction Type 1 diabetes (T1D) is an autoimmune disease characterized by immune destruction of insulin-producing pancreatic β cells. This leads to dysfunctional regulation of blood glucose levels in T1D patients. The destruction of β cells of Langerhans islets is caused by infiltration of dendritic cells, macrophages and T lymphocytes. The destruction of β cells starts with an autoimmune process that is followed by massive destruction of β cells later on. Autoantibodies against T1D-specific antigens are present in serum and can be detected in the early stage of the disease (Ounisis-Benkalha & Polychronakos, 2008). There are several main types of T1D autoantibodies: islet antibodies, antibodies to insulin (IAA), glutamic acid decarboxilase (GADA) and tyrosine phosphatise IA-2. In the last few years antibodies to zinc transporter (ZnT8) have been added to this group (Mehers & Gillespie, 2008). It is generally accepted that T1D occurs as a result of genetic and environmental factors when presence of many alleles combined with effects of numerous environmental factors lead to disease development (Pociot et al., 2010). Research of T1D genetic basis and environmental factors has increased dramatically in the last two decades. Today it is considered that beside HLA region on chromosome 6q21 that contributes approximately with 40% to T1D development, more than 50 non-HLA genes significantly increase the risk of T1D occurrence (MacFarlane et al., 2009, Ziegler et al., 2010, Concannon et al., 2010). The final aim of genetic research is integration with clinical practice, which is expected once the main understanding of genetic etiology of T1D is achieved. Translation to clinics includes development of genetic-based diagnostic tests, population screening methods and pre Continue reading >>

Shared Genetic Basis For Type 1 Diabetes, Islet Autoantibodies, And Autoantibodies Associated With Other Immune-mediated Diseases In Families With Type 1 Diabetes

Shared Genetic Basis For Type 1 Diabetes, Islet Autoantibodies, And Autoantibodies Associated With Other Immune-mediated Diseases In Families With Type 1 Diabetes

Shared Genetic Basis for Type 1 Diabetes, Islet Autoantibodies, and Autoantibodies Associated With Other Immune-Mediated Diseases in Families With Type 1 Diabetes Caroline A. Brorsson - Herlev Hospital, Technical University of Denmark Flemming Pociot - Herlev Hospital Type 1 diabetes (T1D) is a polygenic autoimmune disease that is often present with autoantibodies directed against pancreatic islet proteins. Many genetic susceptibility loci are shared with other autoimmune or immune-mediated diseases that also cosegregate in families with T1D. The aim of this study was to investigate whether susceptibility loci identified in genome-wide association studies (GWAS) of T1D were also associated with autoantibody positivity in individuals with diabetes. Fifty single nucleotide polymorphisms (SNPs) were genotyped in 6,556 multiethnic cases collected by the Type 1 Diabetes Genetics Consortium (T1DGC). These were tested for association with three islet autoantibodies-against autoantibodies to GAD (GADA), IA-2 (IA-2A), and zinc transporter 8 (ZnT8A)-and autoantibodies against thyroid peroxidase (TPOA) in autoimmune thyroid disease, gastric parietal cells (PCA) in autoimmune gastritis, transglutaminase (TGA) in celiac disease, and 21-hydroxylase (21-OHA) in autoimmune hypoadrenalism. In addition to the MHC region, we identify SNPs in five susceptibility loci (IFIH1, PTPN22, SH2B3, BACH2, and CTLA4) as significantly associated with more than one autoantibody at a false discovery rate less than 5%. IFIH1/2q24 demonstrated the most unrestricted association, as significant association was demonstrated for PCA, TPOA, GADA, 21-OHA, and IA-2A. In addition, 11 loci were significantly associated with a single autoantibody. National Institute of Diabetes and Digestive and Kidney Diseases N Continue reading >>

The Genetic Architecture Of Type 1 Diabetes

The Genetic Architecture Of Type 1 Diabetes

Open Access Abstract : Type 1 diabetes (T1D) is classically characterised by the clinical need for insulin, the presence of disease-associated serum autoantibodies, and an onset in childhood. The disease, as with other autoimmune diseases, is due to the interaction of genetic and non-genetic effects, which induce a destructive process damaging insulin-secreting cells. In this review, we focus on the nature of this interaction, and how our understanding of that gene–environment interaction has changed our understanding of the nature of the disease. We discuss the early onset of the disease, the development of distinct immunogenotypes, and the declining heritability with increasing age at diagnosis. Whilst Human Leukocyte Antigens (HLA) have a major role in causing T1D, we note that some of these HLA genes have a protective role, especially in children, whilst other non-HLA genes are also important. In adult-onset T1D, the disease is often not insulin-dependent at diagnosis, and has a dissimilar immunogenotype with reduced genetic predisposition. Finally, we discuss the putative nature of the non-genetic factors and how they might interact with genetic susceptibility, including preliminary studies of the epigenome associated with T1D. 1. Introduction The aetiology of Type 1 diabetes (T1D), like most common chronic diseases, is complex and results from the interaction of genetic and environmental factors. That interplay takes place in a sequence that is true for all autoimmune diseases, and encompasses genetic susceptibility, tissue inflammation, and clinical disease [1,2]. This sequence is characterised by a diminished risk of progression at each transition, with more subjects having genetic risk (roughly 20%) than have inflammation (roughly 14%), and more having inflam Continue reading >>

Genetic And Epigenetic Factors In Etiology Of Diabetes Mellitus Type 1

Genetic And Epigenetic Factors In Etiology Of Diabetes Mellitus Type 1

Abstract Diabetes mellitus type 1 (T1D) is a complex disease resulting from the interplay of genetic, epigenetic, and environmental factors. Recent progress in understanding the genetic basis of T1D has resulted in an increased recognition of childhood diabetes heterogeneity. After the initial success of family-based linkage analyses, which uncovered the strong linkage and association between HLA gene variants and T1D, genome-wide association studies performed with high-density single-nucleotide polymorphism genotyping platforms provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remains to be performed. T1D is one of the most heritable common diseases, and among autoimmune diseases it has the largest range of concordance rates in monozygotic twins. This fact, coupled with evidence of various epigenetic modifications of gene expression, provides convincing proof of the complex interplay between genetic and environmental factors. In T1D, epigenetic phenomena, such as DNA methylation, histone modifications, and microRNA dysregulation, have been associated with altered gene expression. Increasing epidemiologic and experimental evidence supports the role of genetic and epigenetic alterations in the etiopathology of diabetes. We discuss recent results related to the role of genetic and epigenetic factors involved in development of T1D. The Editorial Board of the Section on Pediatric Trainees Monthly Feature is proud to feature an article by Dr Kavitha Selvaraj, who suggests that the effects of toxic stress can be combated through the development of physician–teacher partnerships. Her article concluded our series of featured essays on the Advocacy Campaign for 2016–2017. Catherine Spaulding, MD, Editor, Pediatrics, Continue reading >>

Defining The Genetic Contribution Of Type 2 Diabetes Mellitus

Defining The Genetic Contribution Of Type 2 Diabetes Mellitus

Diabetes mellitus (DM) affects over 150 million people world wide, with a prevalence that varies markedly from population to population.1 Estimates predict that almost 300 million people will suffer from DM by 2025 (fig 1) with the vast majority being cases of diabetes mellitus type 2. Many risk factors have been identified which influence the prevalence (total number of cases as a percentage of the total population) or incidence (total number of new cases per year as a percentage of the total population). Factors of particular importance are a family history of diabetes mellitus, age, overweight, increased abdominal fat, hypertension, lack of physical exercise, and ethnic background. Several biochemical markers have also been identified as risk factors, including fasting hyperinsulinaemia, increased fasting proinsulin, and decreased HDL cholesterol.2 Both diabetes mellitus types 1 and 2 show a familial predisposition, which is a strong indication for the involvement of genes in people's susceptibility to the disease. However, the aetiology underlying types 1 and 2 is different and different genes are likely to be involved in each type of diabetes mellitus. The following discussion focuses on a genetic dissection of type 2 diabetes mellitus. The two most common forms of diabetes mellitus, type 1 and type 2, are both characterised by raised plasma glucose levels. Normal glucose homeostasis depends on the balance between glucose production by the liver and kidneys and glucose uptake by the brain, kidneys, muscles, and adipose tissue. Insulin, the predominant anabolic hormone involved, increases the uptake of glucose from the blood, enhances its conversion to glycogen and triglyceride, and also increases glucose oxidation. Plasma glucose levels are normally kept within a s 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 >>

11111 Fact Sheet 48|diabetes Types 1 And 2 And Inherited Predisposition

11111 Fact Sheet 48|diabetes Types 1 And 2 And Inherited Predisposition

 WHAT IS DIABETES? Diabetes mellitus (commonly known as diabetes) refers to a group of conditions which cause high levels of glucose (a form of sugar) in the blood. Glucose provides the energy that cells need to function. The level of glucose in an individual’s blood is carefully regulated by the hormone insulin. Insulin is produced in the pancreas and its role is to keep the levels of glucose balanced - not too high and not too low - as both extremes are dangerous and can disrupt the body’s chemical processes. There are two major forms of diabetes:  Type 1 (insulin dependent diabetes mellitus: IDDM)  Type 2 (non-insulin dependent diabetes mellitus: NIDDM). There is also another rarer type of diabetes called mature onset diabetes of the young (MODY). All of these forms of diabetes have different symptoms and a different genetic basis. Type 1 diabetes (IDDM) Type 1 diabetes is a chronic autoimmune disease, where the immune system destroys the insulin- producing cells of the pancreas. About 10% to 15% of people with diabetes in Australia have type 1 diabetes. The general population risk for developing type 1 diabetes is around 1 in 1000. The condition is usually first seen in childhood or adolescence and so is sometimes called juvenile diabetes. The risk of type 1 diabetes in 0-14 year olds around 1 in 750. It can, however, occur at any age and onset after the age of 20 years occurs in 50% of cases. Symptoms include:  thirst  frequent urination  weight loss  fatigue  blurred vision  sugar in the urine Insulin medication (usually by injection) is necessary to provide the body with insulin, and thus type 1 diabetes is described as insulin- dependent diabetes (IDDM). In about 90% of cases, individua Continue reading >>

Which Type Of Diabetes Is More Likely To Be Inherited And Why?

Which Type Of Diabetes Is More Likely To Be Inherited And Why?

Yahoo!-ABC News Network | 2018 ABC News Internet Ventures. All rights reserved. Which Type Of Diabetes Is More Likely To Be Inherited And Why? DIRECTOR OF THE DIVISION OF ENDOCRINOLOGY, UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE Question: Which type of diabetes is more likely to be inherited and why? Answer: Type 1 diabetes typically occurs in childhood, while type 2 diabetes usually develops in adults. However, some adults develop a form of diabetes that looks very similar to type 1 diabetes, and now with the huge increase in obesity, many children and adolescents are getting type 2 diabetes. Now, both type 1 and type 2 diabetes have a genetic component; that means of course, that they tend to run in families. However, we often regard diseases that develop in childhood as being more likely to be due to genetics. But this is not the case for diabetes, and in fact, studies show that type 2, which mostly commonly develops in adulthood, seems to have a greater genetic basis than the childhood form of type 1 diabetes. For example, as you know, identical twins share 100 percent of their genetic material; however, if one twin has type 1 diabetes, the chance of that the other twin will develop it is only 10 to 20 percent. In contrast, if one twin has type 2, or the adult form of diabetes, the other twin has up to a 90 percent chance of developing type 2 diabetes. In type 2 diabetes, we know that overeating and lack of physical activity are very important contributors. Meanwhile, for type 1 diabetes, it's more the exposure to toxins in the environment, possibly viruses, and other external factors that can increase risk to this form of diabetes. Continue reading >>

Common Genetic Basis Between Type 1 And Type 2 Diabetes Mellitus Indicated By Interview-based Assessment Of Family History

Common Genetic Basis Between Type 1 And Type 2 Diabetes Mellitus Indicated By Interview-based Assessment Of Family History

Volume 66, Supplement , December 2004, Pages S91-S95 Common genetic basis between type 1 and type 2 diabetes mellitus indicated by interview-based assessment of family history Author links open overlay panel TomomiFujisawa HiroshiIkegami Get rights and content To investigate the intrafamilial clustering of type 1 and type 2 diabetes, an interview-based assessment of family history of diabetes was conducted. Outpatients with either type 1 (n = 23) or type 2 diabetes (n = 124), and non-diabetic subjects (n = 118) received an interview regarding the diabetic status of each of their family members. In patients with type 1 diabetes, 22% (5 out of 23) had a parental history of diabetes, and diabetes in these 5 parents was assessed as type 2 diabetes mellitus. The prevalence of parental diabetes in the type 1 diabetic probands (22%) was significantly higher (P < 0.05) than that in non-diabetic probands (7%, 8 out of 118). In probands with type 2 diabetes, the prevalence of parental diabetes was 39% (48 out of 124), which was significantly higher (P < 0.0005) than that in the non-diabetic probands (7%). In the type 2 diabetic probands, no significant difference was noted in the prevalence between paternal (19%, 23 out of 124) and maternal diabetes (23%, 28 out of 124), suggesting no preferential inheritance of maternal diabetes in this population. The present interview-based assessment of family history of diabetes suggested a common genetic basis between type 1 and type 2 diabetes. Continue reading >>

Genetic Basis Of Type 1 Diabetes: Similarities And Differences Between East And West

Genetic Basis Of Type 1 Diabetes: Similarities And Differences Between East And West

Genetic Basis of Type 1 Diabetes: Similarities and Differences between East and West Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine, Osaka-sayama, Osaka 589-8511, Japan Address correspondence to: Hiroshi Ikegami, e-mail: [email protected] Received 2008 Jul 15; Revised 2008 Aug 13; Accepted 2008 Aug 15. Copyright 2008, SBDR - Society for Biomedical Diabetes Research This article has been cited by other articles in PMC. Type 1 diabetes is a multifactorial disease caused by a complex interaction of genetic and environmental factors. The genetic factors involved consist of multiple susceptibility genes, at least five of which, HLA, INS, CTLA4, PTPN22 and IL2RA/CD25, have been shown to be associated with type 1 diabetes in Caucasian (Western) populations, as has recently been confirmed by genome-wide association studies. It has been proposed, however, that the contribution of these genes to type 1 diabetes susceptibility may be different in Asian (Eastern) populations. HLA and INS genes are consistently associated with type 1 diabetes in both Caucasian and Asian populations, but apparent differences in disease-associated alleles and haplotypes are observed between Japanese and Caucasian subjects. The association of CTLA4 with type 1 diabetes is concentrated in a subset of patients with autoimmune thyroid disease (AITD) in both Japanese and Caucasian populations, while the association of PTPN22 with type 1 diabetes in Japanese and most Asian populations is not as clear as in Caucasians. IL2RA/CD25 genes seem to be similarly distributed in type 1 diabetes patients in the two populations, whereas genetic heterogeneity may exist regarding SUMO4, with an association of the M55V variant with type 1 diabetes observed in Asians, but Continue reading >>

Genetics Of Diabetes And Its Complications

Genetics Of Diabetes And Its Complications

Genetics of Diabetes Type 1 diabetes is the third most prevalent chronic disease of childhood, affecting up to 0.4% of children in some populations by age 30 yr, with an overall lifetime risk of nearly 1% (1,2). It is believed that a large proportion of cases of type 1 diabetes result from the autoimmune destruction of the pancreatic β cells, leading to complete dependence on exogenous insulin to regulate blood glucose levels (3). Type 1 diabetes is strongly clustered in families with an overall genetic risk ratio (the prevalence in siblings of a proband relative to the population prevalence, λS) of approximately 15 (4). (This compares with the less familial but more prevalent type 2 diabetes with λS of approximately 2). At least one locus that contributes strongly to this familial clustering resides within the MHC on chromosome 6p21, which accounts for nearly 40% of the observed familial clustering of type 1 diabetes, with a locus-specific genetic risk ratio (λS) of approximately 3 (5). In a recent analysis of data from three previous genomewide scans (United States, United Kingdom, and Scandinavia) as well as new families collected for the Type 1 Diabetes Genetics Consortium (1435 multiplex families provided evidence for linkage of type 1 diabetes to the MHC (IDDM1), insulin (INS, IDDM2), a region that contains several genes, including CTLA4 (2q31-q33 [IDDM12 and IDDM7]) and seven other chromosome regions (6). The genetic basis for type 2 diabetes has been difficult to resolve. Unlike type 1 diabetes, in which there seems to be an autoimmune process, type 2 diabetes is a disease of relative rather than absolute insulin deficiency. In type 2 diabetes, the pancreatic β cells become progressively less able to secrete sufficient insulin to maintain normal carbohydrat Continue reading >>

Openaire - Project: The Genetic Basis Of Type 1 Di...

Openaire - Project: The Genetic Basis Of Type 1 Di...

Projects:WT, NIH | The genetic basis of type 1 diabetes autoimmunity (3R01DK061722-02S1) Classical human leukocyte antigens (HLA) genes confer the strongest, but not the only, genetic susceptibility to type 1 diabetes. Killer cell immunoglobulin-like receptors (KIR), on natural killer (NK) cells, bind ligands including class I HLA. We examined presence or absence, with copy number, of KIR loci in 1698 individuals, from 339 multiplex type 1 diabetes families, from the Human Biological Data Interchange, previously genotyped for HLA. Combining family data with KIR copy number inform... Receiver Operating Characteristic Analysis of HLA, CTLA4, and Insulin Genotypes for Type 1 Diabetes Valdes, Ana M.; Varney, Michael D.; Erlich, Henry A.; Noble, Janelle A. (2013) Projects: NIH | The genetic basis of type 1 diabetes autoimmunity (3R01DK061722-02S1) , NIH | Type 1 Diabetes Genetics Consortium (1U01DK062418-01) OBJECTIVE This study assessed the ability to distinguish between type 1 diabetesaffected individuals and their unaffected relatives using HLA and single nucleotide polymorphism (SNP) genotypes. RESEARCH DESIGN AND METHODS Eight models, ranging from only the high-risk DR3/DR4 genotype to all significantly associated HLA genotypes and two SNPs mapping to the cytotoxic T-cellassociated antigen-4 gene (CTLA4) and insulin (INS) genes, were fitted to high-resolution class I and class II HLA genot... Use of class I and class II HLA loci for predicting age at onset of type 1 diabetes in multiple populations Valdes, A. M.; Erlich, H. A.; Carlson, J.; Varney, M.; Moonsamy, P. V.; Noble, J. A. (2012) Projects: EC | TREAT OA (200800) , WT, NIH | The genetic basis of type 1 diabetes autoimmunity (3R01DK061722-02S1) The mitochondrial theory of ageing proposes that damage to mitochond Continue reading >>

The Genetic Basis For Type 1 Diabetes.

The Genetic Basis For Type 1 Diabetes.

1. Br Med Bull. 2008;88(1):115-29. doi: 10.1093/bmb/ldn045. (1)Medical School Unit, Southmead Hospital, Bristol BS105NB, UK. BACKGROUND: Type 1 diabetes (T1D) is characterized by autoimmune destruction ofinsulin-producing beta-cells in the pancreas resulting from the action ofenvironmental factors on genetically predisposed individuals. The increasingincidence over recent decades remains unexplained, but the capacity ofidentifying infants at highest genetic risk has become an increasing requirement for potential therapeutic intervention trials.SOURCES OF DATA: Literature searches on T1D and genes were carried out, and keypapers since the 1970s were highlighted for inclusion in this review.AREAS OF AGREEMENT: Early genetic studies identified the most important regionfor genetic susceptibility to T1D-the human leukocyte antigen genes on chromosome6; later shown to contribute approximately half of the genetic determination ofT1D. The other half is made up of multiple genes, each having a limitedindividual impact on genetic susceptibility.AREAS OF CONTROVERSY: Historically, there have been many controversial geneticassociations with T1D, mostly caused by underpowered case-control studies butthese are now decreasing in frequency. AREAS OF GROWTH: The functional effect of each gene associated with T1D must be investigated to determine its usefulnessboth in risk assessment and as a potential therapeutic target.AREAS TIMELY FOR DEVELOPING RESEARCH: Recently identified copy number variants inDNA and epigenetic modifications (heritable changes not associated with changesin the DNA sequence) are also likely to play a role in genetic susceptibility to T1D. Continue reading >>

Type 1 Diabetes

Type 1 Diabetes

Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels. In this form of diabetes, specialized cells in the pancreas called beta cells stop producing insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. Lack of insulin results in the inability to use glucose for energy or to control the amount of sugar in the blood. Type 1 diabetes can occur at any age; however, it usually develops by early adulthood, most often starting in adolescence. The first signs and symptoms of the disorder are caused by high blood sugar and may include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, tingling or loss of feeling in the hands and feet, and weight loss. These symptoms may recur during the course of the disorder if blood sugar is not well controlled by insulin replacement therapy. Improper control can also cause blood sugar levels to become too low (hypoglycemia). This may occur when the body's needs change, such as during exercise or if eating is delayed. Hypoglycemia can cause headache, dizziness, hunger, shaking, sweating, weakness, and agitation. Uncontrolled type 1 diabetes can lead to a life-threatening complication called diabetic ketoacidosis. Without insulin, cells cannot take in glucose. A lack of glucose in cells prompts the liver to try to compensate by releasing more glucose into the blood, and blood sugar can become extremely high. The cells, unable to use the glucose in the blood for energy, respond by using fats instead. Breaking down fats to obtain energy produces waste products called ketones, which can build up to toxic levels in people with type 1 diabetes, resulting in diabetic ketoacidosis. Affected individuals may begin breathin Continue reading >>

Omim Entry - % 222100 - Diabetes Mellitus, Insulin-dependent; Iddm

Omim Entry - % 222100 - Diabetes Mellitus, Insulin-dependent; Iddm

The type of diabetes mellitus called IDDM is a disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. It is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian populations (Todd, 1990). Genetic studies of IDDM have focused on the identification of loci associated with increased susceptibility to this multifactorial phenotype. The classical phenotype of diabetes mellitus is polydipsia, polyphagia, and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. The term diabetes mellitus is not precisely defined and the lack of a consensus on diagnostic criteria has made its genetic analysis difficult. Diabetes mellitus is classified clinically into 2 major forms of the primary illness, insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM; 125853), and secondary forms related to gestation or medical disorders. Appearance of the IDDM phenotype is thought to require a predisposing genetic background and interaction with other environmental factors. Rotter and Rimoin (1978) hypothesized that there are at least 2 forms of IDDM: a B8 (DR3)-associated form characterized by pancreatic autoimmunity, and a B15-associated form characterized by antibody response to exogenous insulin. Interestingly, the DR3 and DR4 alleles seem to have a synergistic effect on the predisposition to IDDM based on the greatly increased risk observed in persons having both the B8 and B15 antigens (Svejgaard and Ryder, 1977). Rotter and Rimoin (1979) hypothesized a combined form. Tolins and Raij (1988) cited clinical and experimental Continue reading >>

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