Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases

Becker, Kevin G.; Simon, Richard; Bailey-Wilson, Joan E.; Freidlin, Boris; Biddison, William E.; McFarland, Henry F.; Trent, Jeffrey M.

doi:10.1073/pnas.95.17.9979

Cited by 541 publications

(342 citation statements)

References 63 publications

(54 reference statements)

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“…25 While some of our linkage peaks indicate the likely regions containing loci conferring susceptibility to multiple sclerosis specifically, others may indicate regions containing loci conferring susceptibility to autoimmunity in general. 26 With this hypothesis in mind there is interesting concordance between our results and those from studies in other autoimmune diseases.…”

Section: Discussionsupporting

confidence: 88%

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis

et al. 2002

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Section: Discussionsupporting

confidence: 88%

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis

et al. 2002

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“…Supplementary Table 1). This commonality between AIDs is also reflected in genome-wide linkage scans 14 and/or association studies revealing shared genetic factors elsewhere in the genome, most notably variants of the CTLA4 and PTPN22 genes. 15 This has led to the belief that, despite a wide variety of clinical manifestations, AIDs share certain biological features that are common to the autoimmune process.…”

Section: Introductionmentioning

confidence: 94%

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

et al. 2008

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The main genetic predisposition to type 1 diabetes (T1D) is known to be conferred by the HLA-DRB1, -DQA1 and -DQB1 genes in the major histocompatibility complex (MHC). Other genetic factors within this complex are known to contribute, but their identity has often been controversial. This picture is shared with several other autoimmune diseases (AIDs). Moreover, as common genetic factors are known to exist between AIDs, associations reported with other AIDs may also be involved in T1D. In this study, we have used these observations in a candidate gene approach to look for additional MHC risk factors in T1D. Using complementary conditional methods (involving conditional logistic regression and family-based haplotype tests) and analyses of linkage disequilibrium (LD) patterns, we confirmed association for alleles of the HLA-A and HLA-B genes and found preliminary evidence for a novel association of a single-nucleotide polymorphism (rs2259571) in the AIF1 gene, independent of the DRB1-DQA1-DQB1 genes and of each other. However, no evidence of independent associations for a number of previously suggested candidate polymorphisms was detected. Our results illustrate the importance of a comprehensive adjustment for LD effects when performing association studies in this complex.

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“…It is well known that HLA region genes are associated with many other autoimmune or immune-related disorders in addition to Type I diabetes [126]. Recent research indicates that several of the non-HLA regions linked to Type I diabetes also show linkage to other autoimmune diseases, suggesting common pathogenic pathways shared by Type I diabetes and these other disorders [127,128]. For example, the IDDM3 region on chromosome 15q26 has been reported to be linked to coeliac disease [129,130], the IDDM6 region on chromosome 18q21 has been reported to be linked to Graves disease [131] as well as multiple sclerosis and rheumatoid arthritis [69], the IDDM8 region on chromosome 6q27 has been reported to be linked to rheumatoid arthritis [132], the IDDM12 (CTLA4) region on chromosome 2q33 has been reported to be linked to coeliac disease [133,134], Graves disease [78,135], multiple sclerosis [136] and rheumatoid arthritis [137,138], the IDDM16 region on chromosome 14q32 has been reported to be linked to multiple sclerosis [139], and the chromosome 1q42 region containing an unnamed diabetes locus has been reported to be linked to systemic lupus erythematosus [140,141] (for additional examples, see [128]).…”

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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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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Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases

Cited by 541 publications

References 63 publications

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

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

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