Genetics Of Type 1 Diabetes Mellitus
Genes and Immunity volume 3, pages 235249 (2002) This work was in part supported by the EU BioMed 2 Programme (grant no. BMH4CT972311), Novo Nordisk A/S, The Danish Diabetes Association, and the DANDY Foundation. Support from the Juvenile Diabetes Foundation International is also acknowledged. At least 20 different chromosomal regions have been linked to type 1 diabetes (T1D) susceptibility in humans, using genome screening, candidate gene testing, and studies of human homologues of mouse susceptibility genes. The largest contribution from a single locus (IDDM1) comes from several genes located in the MHC complex on chromosome 6p21.3, accounting for at least 40% of the familial aggregation of this disease. Approximately 30% of T1D patients are heterozygous for HLA-DQA1*0501DQB1*0201/DQA1*0301DQB1*0302 alleles (formerly referred to as HLA-DR3/4 and for simplification usually shortened to HLA-DQ2/DQ8), and a particular HLA-DQ6 molecule (HLA-DQA1*0102DQB1*0602) is associated with dominant protection from the disease. There is evidence that certain residues important for structure and function of both HLA-DQ and DR peptide-binding pockets determine disease susceptibility and resistance. Independent confirmation of the IDDM2 locus on chromosome 11p15.5 has been achieved in both case-control and family-based studies, whereas associations with the other potential IDDM loci have not always been replicated. Several possibilities to explain these variable results from different studies are discussed, and a key factor affecting both linkage and association studies is that the genetic basis of T1D susceptibility may differ between ethnic groups. Some future strategies to address these problems are proposed. These include increasing the sample size in homogenous ethnic groups, high Continue reading >>
Diabetes Mellitus Type 1 Inheritance
Type 1 diabetes is an inherited condition and individuals with a first degree relative who has the condition are at an increased risk of developing the condition. Details regarding the risk of inheriting type 1 diabetes are given below: In men with type 1 diabetes, the risk of their child also developing the condition is one in 17. In women with type 1 diabetes who have their baby before the age of 25, the risk of the child developing the condition is one in 25. If she has her baby after the age of 25, the risk falls to 1 in 100. If both parents have type 1 diabetes, the risk of the condition developing in offspring varies between 1 in 4 and 1 in 10. The risks are somewhat increased if one of the parents developed type 1 diabetes before the age of 11. Around 1 in 7 people with type 1 diabetes suffer from a condition called type 2 polyglandular autoimmune syndrome and these individuals have parathyroid and adrenal gland disorders in addition to type 1 diabetes. If one of the parents has type 2 polyglandular autoimmune syndrome, the risk that the child will inherit the condition, including type 1 diabetes, is 50%. Genes associated with type 1 diabetes Some genes have repeatedly been identified in people with type 1 diabetes. Among white individuals, examples of such genes include the HLA-DR3 or HLA-DR4 genes. Carrying these genes raises the risk that offspring will inherit type 1 diabetes. Children born with the HLADR3/4-DQ8 genotype make up nearly 50% of all children who develop type 1 diabetes before they are 5 years of age. Some studies on other ethnic groups have shown that similar risks are associated with the HLA-DR7 genotype among African Americans and with the HLA-DR9 gene among Japanese individuals. Genetic studies have also located HLA class II genes at 6p21 and Continue reading >>
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- Postprandial Blood Glucose Is a Stronger Predictor of Cardiovascular Events Than Fasting Blood Glucose in Type 2 Diabetes Mellitus, Particularly in Women: Lessons from the San Luigi Gonzaga Diabetes Study
Is Type 1 Diabetes Genetic/hereditary? | Causes & Treatment - Dlife
When left uncontrolled, high blood sugar can also cause other complications, affecting the eyes, nerves, kidneys, and cardiovascular system.[1], [4] The difference between type 1 and type 2 diabetes is that in type 1, the body does not produce insulin at all; this is why it is called insulin dependent diabetes. In type 2 diabetes, the body produces insulin but the cells are not able to utilize the insulin produced; this is why it is commonly referred to as insulin resistant diabetes. Over time, the bodys cells can develop insulin resistance in type 1 diabetes, too.[1],[5] Diabetes is diagnosed by testing the level of blood sugar or A1C (glycated hemoglobin). An A1C reading measures the three-month average plasma glucose concentration in the blood. Type 1 diabetes can be distinguished from type 2 by testing for the presence of autoantibodies (a type of protein produced by an individuals immune system directed against one or more of the individuals own proteins).[6],[7] When specific autoantibodies are found, a doctor can make the diagnosis of type 1 diabetes. Type 1 diabetes is a rarer form of diabetes than type 2. Type 1 diabetes accounts for only five to 10 percent of all diabetes cases. Although it can occur at any age, it is more common in children and adolescents less than 15 years of age. This is why the condition was previously coined juvenile diabetes.[8],[9] The occurrence is similar in men and women, although in children it is more common in girls. Type 1 diabetes most commonly occurs during puberty. Because girls typically enter puberty earlier than boys, the condition is often diagnosed earlier in girls. After puberty, the incidence rate drops in women but continues to occur in men between the ages of 29 and 35. More than 500,000 children are currently livin Continue reading >>
Type 1 Diabetes Risk Factors
There are several risk factors that may make it more likely that you’ll develop type 1 diabetes—if you have the genetic marker that makes you susceptible to diabetes. That genetic marker is located on chromosome 6, and it’s an HLA (human leukocyte antigen) complex. Several HLA complexes have been connected to type 1 diabetes, and if you have one or more of those, you may develop type 1. (However, having the necessary HLA complex is not a guarantee that you will develop diabetes; in fact, less than 10% of people with the “right” complex(es) actually develop type 1.) Other risk factors for type 1 diabetes include: Viral infections: Researchers have found that certain viruses may trigger the development of type 1 diabetes by causing the immune system to turn against the body—instead of helping it fight infection and sickness. Viruses that are believed to trigger type 1 include: German measles, coxsackie, and mumps. Race/ethnicity: Certain ethnicities have a higher rate of type 1 diabetes. In the United States, Caucasians seem to be more susceptible to type 1 than African-Americans and Hispanic-Americans. Chinese people have a lower risk of developing type 1, as do people in South America. Geography: It seems that people who live in northern climates are at a higher risk for developing type 1 diabetes. It’s been suggested that people who live in northern countries are indoors more (especially in the winter), and that means that they’re in closer proximity to each other—potentially leading to more viral infections. Conversely, people who live in southern climates—such as South America—are less likely to develop type 1. And along the same lines, researchers have noticed that more cases are diagnosed in the winter in northern countries; the diagnosis rate Continue reading >>
Genetics And Type 1 Diabetes
If you have type 1 diabetes, you might wonder if your child would get it, too. Or if one of your parents has it, what it means for you. Your genes definitely play a role in type 1, a less common form of diabetes that’s often diagnosed in children and young adults. But they’re not the whole story. Like much in life, it’s a mix of nature and nurture. Your environment, from where you grow up to the foods you eat, also matters. Researchers don’t know exactly how -- and how much -- all those things affect your chances of getting the disease. Your genes set the stage, but you can’t be certain how it'll all play out. There’s no diabetes gene that gets turned on or off to give you type 1. Instead, a bunch of them play a role, including a dozen or so that have the biggest say: the HLA genes. They make proteins your immune system uses to keep you healthy. Since type 1 diabetes is an autoimmune disease -- your body destroys the cells that make insulin -- it makes sense that HLA genes are front and center. There are thousands of versions of them in the human gene pool. Which ones you get from your parents affect your chances of diabetes in a big way. Some make you more likely to get it, while others can help protect you from it. You have type 1 if your body makes little or no insulin, a hormone that helps your body turn sugar into energy. Certain genes are more common in one group of people than in another. That’s why race and ethnicity affect things, too. For example, white people are more likely to have type 1 diabetes than others. But even if you have genes that make you more likely to get type 1, that doesn’t mean you definitely will. Even with identical twins -- who have the same exact genes -- sometimes one gets it and the other doesn’t. That’s where the e Continue reading >>
Genetic Basis For Type 1 Diabetes | British Medical Bulletin | Oxford Academic
Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing -cells in the pancreas resulting from the action of environmental factors on genetically predisposed individuals. The increasing incidence over recent decades remains unexplained, but the capacity of identifying infants at highest genetic risk has become an increasing requirement for potential therapeutic intervention trials. Literature searches on T1D and genes were carried out, and key papers since the 1970s were highlighted for inclusion in this review. Early genetic studies identified the most important region for genetic susceptibility to T1Dthe human leukocyte antigen genes on chromosome 6; later shown to contribute approximately half of the genetic determination of T1D. The other half is made up of multiple genes, each having a limited individual impact on genetic susceptibility. Historically, there have been many controversial genetic associations with T1D, mostly caused by underpowered casecontrol studies but these are now decreasing in frequency. The functional effect of each gene associated with T1D must be investigated to determine its usefulness both in risk assessment and as a potential therapeutic target. Recently identified copy number variants in DNA and epigenetic modifications (heritable changes not associated with changes in the DNA sequence) are also likely to play a role in genetic susceptibility to T1D. type 1 diabetes , genes , HLA class II , islet autoantibodies The immune system protects by being able to specifically differentiate between host cells and infectious agents. In autoimmunity, however, this system breaks down: for instance, in type 1 diabetes (T1D), insulin-producing -cells are subjects to specific attack by the host immune system. T1D is often co Continue reading >>
- Practical Approach to Using Trend Arrows on the Dexcom G5 CGM System for the Management of Adults With Diabetes | Journal of the Endocrine Society | Oxford Academic
- Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes
- Genetic Screening for the Risk of Type 2 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 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 >>
Genetic Basis For Type 1 Diabetes | British Medical Bulletin | Oxford Academic
Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing -cells in the pancreas resulting from the action of environmental factors on genetically predisposed individuals. The increasing incidence over recent decades remains unexplained, but the capacity of identifying infants at highest genetic risk has become an increasing requirement for potential therapeutic intervention trials. Literature searches on T1D and genes were carried out, and key papers since the 1970s were highlighted for inclusion in this review. Early genetic studies identified the most important region for genetic susceptibility to T1Dthe human leukocyte antigen genes on chromosome 6; later shown to contribute approximately half of the genetic determination of T1D. The other half is made up of multiple genes, each having a limited individual impact on genetic susceptibility. Historically, there have been many controversial genetic associations with T1D, mostly caused by underpowered casecontrol studies but these are now decreasing in frequency. The functional effect of each gene associated with T1D must be investigated to determine its usefulness both in risk assessment and as a potential therapeutic target. Recently identified copy number variants in DNA and epigenetic modifications (heritable changes not associated with changes in the DNA sequence) are also likely to play a role in genetic susceptibility to T1D. type 1 diabetes , genes , HLA class II , islet autoantibodies The immune system protects by being able to specifically differentiate between host cells and infectious agents. In autoimmunity, however, this system breaks down: for instance, in type 1 diabetes (T1D), insulin-producing -cells are subjects to specific attack by the host immune system. T1D is often co Continue reading >>
- Practical Approach to Using Trend Arrows on the Dexcom G5 CGM System for the Management of Adults With Diabetes | Journal of the Endocrine Society | Oxford Academic
- Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes
- Genetic Screening for the Risk of Type 2 Diabetes
About Type 1 Diabetes
Type 1 diabetes is less common than type 2 diabetes. In the past, type 1 diabetes was called juvenile diabetes, juvenile-onset diabetes, or insulin-dependent diabetes. Today we realize those terms aren't accurate. People can develop type 1 as adults, children can develop type 2, and people with type 2 might need to take insulin shots. Type 1 diabetes is known as an autoimmune disease. It happens because a person's immune system destroys the body's beta cells, which make insulin and release it into the blood stream. These cells are located in an organ called the pancreas. When the immune system destroys the beta cells, the body stops being able to make insulin. Signs of type 1 diabetes start to show up when half or more of the beta cells have been destroyed. People who have type 1 diabetes will begin to take insulin shots right away, to replace the insulin their bodies no longer make. Type 1 diabetes is inherited, which means a group of genes that can lead to type 1 diabetes is passed down from mothers and fathers to their children. A person with a parent, brother, or sister with type 1 diabetes has a greater chance of also developing type 1 diabetes. Genes play an important role in determining who gets type 1 diabetes and who doesn't. But they might not be the only influence. Environmental factors, including viruses and allergies, appear to trigger type 1 diabetes in some people who have inherited the genes. These factors can trigger type 1 diabetes at any point in a person's life. That's why some people don't develop type 1 diabetes until they're adults, while others develop it when they're children. The symptoms for type 1 diabetes usually show up over a few days or even a few weeks and are caused by high levels of sugar in the blood. Urinating more than usual. The k Continue reading >>
Genetics Of Type 1 Diabetes: What's Next?
The discovery of the association between HLA in the major histocompatibility complex (MHC) on chromosome 6p21 with type 1 diabetes, but not with type 2 diabetes, suggested that these disease entities were of different genetic background and pathogenesis. The discovery that some individuals with diabetes had autoantibodies in their blood provided additional evidence that type 1 diabetes had an autoimmune origin. Recently, increasing knowledge of the genome, coupled with rapidly improving genotyping technology and availability of increasingly large numbers of samples, has enabled statistically robust, systematic, genome-wide examinations for discovery of loci contributing to type 1 diabetes susceptibility, including within the MHC itself. Currently, there are over 50 non-HLA regions that significantly affect the risk for type 1 diabetes (Many of these regions contain interesting, but previously unrecognized, candidate genes. A few regions contain genes of unknown function or no known annotated genes, suggesting roles for long-distance gene regulatory effects, noncoding RNAs, or unknown mechanisms. Against a background of ever-improving knowledge of the genome, particularly its transcriptional regulation, and with massive advances in sequencing, specific genes, rather than regions that impinge upon type 1 diabetes risk, will be identified soon. Here we discuss follow-up strategies for genome-wide association (GWA) studies, causality of candidate genes, and genetic association in a bioinformatics approach with the anticipation that this knowledge will permit identification of the earliest events in type 1 diabetes etiology that could be targets for intervention or biomarkers for monitoring the effects and outcomes of potential therapeutic agents. The International Type 1 Di Continue reading >>
Genetic Risk Factors For Type 1 Diabetes
Summary Type 1 diabetes is diagnosed at the end of a prodrome of β-cell autoimmunity. The disease is most likely triggered at an early age by autoantibodies primarily directed against insulin or glutamic acid decarboxylase, or both, but rarely against islet antigen-2. After the initial appearance of one of these autoantibody biomarkers, a second, third, or fourth autoantibody against either islet antigen-2 or the ZnT8 transporter might also appear. The larger the number of β-cell autoantibody types, the greater the risk of rapid progression to clinical onset of diabetes. This association does not necessarily mean that the β-cell autoantibodies are pathogenic, but rather that they represent reproducible biomarkers of the pathogenesis. The primary risk factor for β-cell autoimmunity is genetic, mainly occurring in individuals with either HLA-DR3-DQ2 or HLA-DR4-DQ8 haplotypes, or both, but a trigger from the environment is generally needed. The pathogenesis can be divided into three stages: 1, appearance of β-cell autoimmunity, normoglycaemia, and no symptoms; 2, β-cell autoimmunity, dysglycaemia, and no symptoms; and 3, β-cell autoimmunity, dysglycaemia, and symptoms of diabetes. The genetic association with each one of the three stages can differ. Type 1 diabetes could serve as a disease model for organ-specific autoimmune disorders such as coeliac disease, thyroiditis, and Addison's disease, which show similar early markers of a prolonged disease process before clinical diagnosis. Continue reading >>
Genetics & Diabetes : What's Your Risk?
A school nurse anxiously wants to know if there is a reason why several children from her small grade school have been diagnosed with type 1 (juvenile onset) diabetes. Is it an epidemic? Will there be more cases? Is a recent chicken pox outbreak to blame? A man in his 50s develops type 2 diabetes. His mother developed diabetes in her 60s. Should this man's brother and sister be concerned, too? What about his children's chances of developing diabetes? A married couple wants to have children, but they are concerned because the husband has type 1 diabetes. They wonder what the risk is that their child would have diabetes. A couple has three young children. One of the children develops type 1 diabetes. There's no history of diabetes anywhere in either parent's families. Is this just a fluke? What are the chances the other children will develop diabetes? Chances are if you or a loved one have diabetes, you may wonder if you inherited it from a family member or you may be concerned that you will pass the disease on to your children. Researchers at Joslin Diabetes Center report that, while much has been learned about what genetic factors make one more susceptible to developing diabetes than another, many questions remain to be answered. While some people are more likely to get diabetes than others, and in some ways type 2 (adult onset diabetes) is simpler to track than type 1 (juvenile onset) diabetes, the pattern is not always clear. For more than 20 years researchers in the Epidemiology and Genetics Section at Joslin in Boston (Section Head Andrzej S. Krolewski, M.D., Ph.D., Senior Investigator James H. Warram, M.D., Sc.D., and colleagues) have been studying diabetes incidence and hereditary factors. They are continuing a scientific journey begun by Elliott P. Joslin, M.D., Continue reading >>
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 >>
Genetics Of Type 1a
Type 1 diabetes is a complex genetic disorder. There are now at least 20 insulin-dependent genes associated with the development of diabetes. Type 1 diabetes is a complex genetic disorder. It occurs more frequently in families in which there are other relatives with type 1 diabetes and other autoimmune conditions. Children have a 5% to 6% chance of developing diabetes if their father has type 1 diabetes, and a 3% to 4% chance if their mother has type 1 diabetes. It is thought that some of the mother’s chromosomal material, or DNA, gets inactivated when passed on to the child, thereby accounting for the difference in the children’s diabetes risk. If a sibling has type 1 diabetes, the risk is 5-6%; however, if the sibling has identical MHC (Major Histocompatibility Complex) haplotypes, the risk increases. When one identical twin has diabetes, the risk of the other twin developing diabetes traditionally has been thought to be about 40%. Recent research suggests that the number may be much higher. A number of genes have been identified that are associated with the development of diabetes. The chromosomal locations of these “diabetes genes” are called inherited susceptibility loci. There are now at least 20 insulin-dependent diabetes mellitus (IDDM) susceptibility loci. The most important are: IDDM 1 (the major histocompatibility complex on chromosome 6) IDDM 2 (the insulin gene locus on chromosome 11) PTPN 22 (the protein tyrosine phosphatase gene) with a mutation at LYP (the lymphocyte-specific phosphatase gene) on chromosome 1 associated with susceptibility to multiple autoimmune disorders IDDM 1 It is estimated that about 40-50% of the risk for type 1 diabetes is associated with the MHC complex or IDDM 1 loci. The MHC genes most associated with diabetes in white Continue reading >>
