Evidence for oligogenic inheritance of type 1 diabetes in a large Bedouin Arab family.

Verge, Charles F.; Vardi, Pnina; Babu, Sunanda; Bao, Fei; Erlich, Henry A.; Bugawan, Teodorica L.; Tiosano, Dov; Yu, Ling; Eisenbarth, George S.; Fain, Pam R.

doi:10.1172/jci3379

Cited by 54 publications

(50 citation statements)

References 25 publications

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“…This same region of chromosome 10 q has also shown some evidence for linkage (MLS 1.1) in 616 families with typical Type I diabetes [83]. Bedouin Arabs have a relatively low overall frequency of Type I diabetes, but tribes with multiple affected persons are not uncommon [86]. This is consistent with their high degree of inbreeding within, but not across, tribes, and suggests that IDDM17 predisposition could be due to a recessive or dose-dependent gene.…”

Section: Is Positional Candidate Mapping Feasible?mentioning

confidence: 57%

“…Such kindreds are very uncommon and could lead to concerns that they are segregating rare mendelian forms of diabetes rather than classical Type I diabetes. However, IDDM17 was localised to chromosome 10q25 by strong linkage to D10S554 (p = 0.00 004) in a large inbred Bedouin Arab extended family with 19 members having insulin-dependent autoimmune diabetes [86]. This same region of chromosome 10 q has also shown some evidence for linkage (MLS 1.1) in 616 families with typical Type I diabetes [83].…”

Section: Is Positional Candidate Mapping Feasible?mentioning

confidence: 99%

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Genetic linkage and association studies of Type I diabetes: challenges and rewards

Field

2002

Diabetologia

104

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Type I diabetes (formerly called insulin-dependent diabetes mellitus) results from the autoimmune destruction of the insulin-producing beta cells of the pancreas. It is now known that Type I diabetes is a genetically complex disease, i. e. a disease caused by multiple genes interacting with non-genetic (environmental and stochastic) factors. Family studies have clearly shown a genetic basis but inheritance of the disease does not follow a simple mendelian single-locus pattern. Population and family studies also suggest that most (perhaps all) affected individuals are genetically predisposed to Type I diabetes, particularly through HLA region genes. However, non-genetic factors appear to be required to precipitate the disease in these genetically susceptible persons because in monozygote (MZ) twin pairs in which one twin has Type I diabetes the MZ twin concordance rate is less than 100 %. It is not clear whether there are any purely genetic cases of Type I Diabetologia (2002) AbstractFamily and twin studies have shown clearly that Type I (insulin-dependent) diabetes mellitus has a genetic basis. However, only within the past decade has it been possible to systematically attempt to identify the genes that increase susceptibility to this disorder using linkage and association analysis of genetic markers distributed across the genome. More than 20 putative diabetes-predisposing genes have been localised in addition to HLA region susceptibility genes detected more than 25 years ago. Unfortunately, the effects of most diabetes-predisposing genes are weak, with the exception of HLA region susceptibility genes (which contribute about half of the genetic risk). The overall effects of diabetes-predisposing genes could be weak because the susceptibility gene occurs in only a small proportion of diabetic patients or the susceptibility gene (although it might be common) produces only a modest increase in risk, probably by acting in concert with other such genes to cause disease. The weak effects of these genes have made them difficult to locate, difficult to confirm in independent studies and difficult to isolate by genetic procedures. This paper summarizes the major challenges that have faced geneticists in mapping Type I diabetes genes, and reviews the progress achieved to date. The rewards of the genetic studies will be twofold: increased understanding of the causes of Type I diabetes, facilitating creation of preventative therapies, and enabling clinicians in the future to use genetic information to predict which children are predisposed to diabetes in order to target them for preventative therapies. [Diabetologia (2002) 45: 21±35]

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Section: Is Positional Candidate Mapping Feasible?mentioning

confidence: 57%

Section: Is Positional Candidate Mapping Feasible?mentioning

confidence: 99%

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Field

2002

Diabetologia

104

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“…Serum samples were measured by radioassay for autoantibodies to the insulin, GAD65, and ICA512 (IA-2) islet cell autoantigens as described. 24 HLA-DRB1, -DQA1 and -DQB1 exon 2 alleles were amplified using PCR and typed with sequence-specific oligonucleotide probes. 25,26 Additionally, 157 samples were genotyped using the DeCode Genetics (Reykjavik, Iceland) multiplex set of 63 MHCspecific microsatellite markers spanning a 9.38 Mb and 5.75 cM region encompassing the extended MHC.…”

Section: Resultsmentioning

confidence: 99%

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

et al. 2007

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Autoimmune diabetes shows extreme variation in age of onset and clinical presentation, although most studies have been done in children with the most severe subtype. Disease risk is strongly associated with HLA-DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2), but it has not been possible to separate the effects of the DR and DQ alleles. We have identified a large Bedouin kindred in which a high prevalence of islet autoimmunity is associated with two different DR3 haplotypes, one carrying the usual DQ2 and the other carrying DQA1*0102-DQB1*0502 (DQ5). Results of prospective follow-up studies indicate that DR3 is associated with the initial activation of islet autoimmunity whereas DQ2 is associated with early-onset and severe clinical disease. The association signals map to a 350-kb interval, thus implicating primary effects for DR3 and DQ2. Overall, our results emphasize the importance of prospective genetic studies that examine the full range of variation in the initiation, progression and expression of autoimmune disease.

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“…IDDM17 maps to the long arm of chromosome 10 (10q25; non-parametric linkage = 4.99, p = 0.00 004) and is associated with a 151 bp allele at the microsatellite marker D10S554. Relatives in the family with HLA DR3 or DR4 plus IDDM17 have a diabetes risk of 40 % [116].…”

Section: Iddm17mentioning

confidence: 99%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immunemediated diabetes is also heterogeneous with ªmono-genicº, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45:605±622]

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Evidence for oligogenic inheritance of type 1 diabetes in a large Bedouin Arab family.

Cited by 54 publications

References 25 publications

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Genetic control of autoimmunity in Type I diabetes and associated disorders

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Evidence for oligogenic inheritance of type 1 diabetes in a large Bedouin Arab family.

Cited by 54 publications

References 25 publications

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Differential effects of DRB1*0301 and DQA1*0501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Genetic control of autoimmunity in Type I diabetes and associated disorders

Contact Info

Product

Resources

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Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity