Non-HLA region genes in insulin dependent diabetes mellitus

Field, L. Leigh

doi:10.1016/s0950-351x(05)80139-9

Cited by 24 publications

(18 citation statements)

References 43 publications

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“…Between 1984 and 1991, more than 20 studies examined serologically-detected Gm allotypes, variants on the constant region of IgG heavy chains, in type 1 diabetes (reviewed in references [45][46][47]. Although none of these studies found direct evidence of linkage or association with diabetes, many reported evidence of IGH region involvement through interaction with HLA genes.…”

Section: Discussionmentioning

confidence: 99%

“…In most datasets, the Gm(1) frequency was higher in HLA-DR3/4 diabetics than in those who were not DR3/4. 45,[48][49][50][51][52] Two discrepant datasets showed other significant Gm-HLA effects. 53,54 Linkage studies have been less common, but overall have suggested increased joint sharing of Gm and HLA haplotypes in diabetic sibpairs.…”

Section: Discussionmentioning

confidence: 99%

“…53,54 Linkage studies have been less common, but overall have suggested increased joint sharing of Gm and HLA haplotypes in diabetic sibpairs. 45,[55][56][57] In one of the few studies examining Gm allotypes for all three polymorphic IgG subclasses, the strongest interaction was a lower frequency of Gm(23) in HLA-DR3/4 diabetics vs non-DR3/4 diabetics or normal controls. 45 Since haplotypes positive for Gm(1) are negative for Gm (23), this finding was consistent with previous studies and suggested that negativity for Gm (23), an IgG2 subclass marker, increases susceptibility to type 1 diabetes in HLA-DR3/4 individuals.…”

Section: Discussionmentioning

confidence: 99%

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Evidence for a locus (IDDM16) in the immunoglobulin heavy chain region on chromosome 14q32.3 producing susceptibility to type 1 diabetes

et al. 2002

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Evidence for a locus (IDDM16) in the immunoglobulin heavy chain region on chromosome 14q32.3 producing susceptibility to type 1 diabetes

et al. 2002

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“…Even the largest Type I diabetes linkage study to date (616 families [83]) could not detect strong evidence for linkage to this region (maximum lod score 0.6). However, application of family-based association analysis using AFBAC [57,111] indicated that the population-based association was not spurious. The INS region studies clearly showed that significant association (linkage disequilibrium) could be detected in the absence of evidence for linkage [111].…”

Section: The Challenges Of Searching For Type I Diabetes Genesmentioning

confidence: 99%

“…However, application of family-based association analysis using AFBAC [57,111] indicated that the population-based association was not spurious. The INS region studies clearly showed that significant association (linkage disequilibrium) could be detected in the absence of evidence for linkage [111]. This could seem paradoxical; however, it has been shown by simulation studies that a susceptibility gene which has a modest effect on disease risk and is common in the general population (many persons are homozygous) could be detectable by association but not by linkage analysis [110].…”

Section: The Challenges Of Searching For Type I Diabetes Genesmentioning

confidence: 99%

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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Dissecting the genetics of Type 1 diabetes: relevance for familial clustering and differences in incidence

Buzzetti

Quattrocchi

Nisticò

1998

Diabetes Metab. Rev.

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A combination of genetic and environmental factors is most likely the cause of Type 1 diabetes. Results from twin data, familial clustering of the disease and difference in incidence according to ethnicity infer the presence of specific disease genes. The genetic component of Type 1 diabetes cannot be classified according to a classical model of inheritance but is due to an interaction between different genes and environmental factors. The major genes are within the HLA region that are responsible for 40% of the genetic susceptibility, although other genes are important (non-HLA genes). To date, more than 10 specific loci have been localized on different chromosomes. The gene involved has been characterized only for two of such loci, IDDM1 and IDDM2, while in the other cases the presence of some susceptibility genes can be envisaged and their identification represents the goal of genetic research in coming years. Fine mapping of the loci will certainly increase our understanding of the genetics of Type 1 diabetes; the limitation in detecting some of the remaining genes by linkage studies can be overcome by association studies. That is possible via the collection of a large number of affected families (over 1000) in homogeneous populations.

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Non-HLA region genes in insulin dependent diabetes mellitus

Cited by 24 publications

References 43 publications

Evidence for a locus (IDDM16) in the immunoglobulin heavy chain region on chromosome 14q32.3 producing susceptibility to type 1 diabetes

Evidence for a locus (IDDM16) in the immunoglobulin heavy chain region on chromosome 14q32.3 producing susceptibility to type 1 diabetes

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

Dissecting the genetics of Type 1 diabetes: relevance for familial clustering and differences in incidence

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