Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?

Windsor, Lydia; Puschendorf, Mareike; Allcock, Richard; Scott, Adrian P.; Sayer, D.; Kucharzak, Ramón; Gut, Ivo; McCann, Vincent J.; Davis, Elizabeth A.; Witt, Campbell S.; Christiansen, Frank; Price, Patricia

doi:10.1038/sj.gene.6364210

Cited by 12 publications

(10 citation statements)

References 24 publications

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“…Warren et al (1991) showed that autistic individuals ( N = 38) and their mothers, but not their fathers, exhibited a significantly higher frequency than controls ( N = 62) of the C4B null allele ( P = 0.03 for autistic subjects, P = 0.01 for mothers). The C4B null allele forms part of the ancestral HLA haplotype 44.1 (B44‐SC30‐DRB1*0401‐DQ7) (Warren et al 1996a; Windsor et al 2005). This finding was replicated in Warren et al (1992) ( N = 21 cases and 62 controls, P = 0.0035 for autistic subjects, P = 0.016 for mothers) and Daniels et al (1995) ( N = 45 cases + parents, and 64 controls; P < 0.001 for autistic subjects and mothers).…”

Section: Resultsmentioning

confidence: 99%

Comparative immunogenetics of autism and schizophrenia

Crespi

Thiselton

2011

Genes, Brain and Behavior

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Autism and schizophrenia are highly heritable neurodevelopmental disorders, each mediated by a diverse suite of genetic and environmental risk factors. Comorbidity and familial aggregation of such neurodevelopmental disorders with other disease-related conditions can provide important insights into their etiology. Epidemiological studies have documented reduced rates of rheumatoid arthritis, a systemic autoimmune condition, in schizophrenia, and recent work has shown increased rates of rheumatoid arthritis in first-degree relatives of autistic individuals, especially mothers. Advances in understanding the genetic basis of rheumatoid arthritis have shown that much of the genetic liability to this condition is due to risk and protective alleles at the HLA DRB1 locus. These data allow robust testing of the hypotheses that allelic variation at DRB1 pleiotropically modulates risk of rheumatoid arthritis, autism and schizophrenia. Systematic review of the literature indicates that reported associations of DRB1 variants with these three conditions are congruent with a pleiotropic model: DRB1*04 alleles have been associated with increased risk of rheumatoid arthritis and autism but decreased risk of schizophrenia, and DRB1*13 alleles have been associated with protection from rheumatoid arthritis and autism but higher risk of schizophrenia. These convergent findings from genetics and epidemiology imply that a subset of autism and schizophrenia cases may be underlain by genetically based neuroimmune alterations, and that analyses of the causes of risk and protective effects from DRB1 variants may provide new approaches to therapy.

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Section: Resultsmentioning

confidence: 99%

Comparative immunogenetics of autism and schizophrenia

Crespi

Thiselton

2011

Genes, Brain and Behavior

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“…Work in T1D identified a microsatellite D6S2223 4.9kb telomeric of DQ in the extended class I region, as being associated with a reduction in the risk conferred by the DR3 extended haplotype on disease [50], with further work narrowing the association to a region encompassing the class III and HLA-B/-C gene regions [51]. Work in the NOD mouse also suggested the presence of independent risk factors within the MHC, independent of the MHC class II [52], with further genetic studies in humans confirming the presence of HLA class II independent T1D susceptibility loci within the class I region [53,54]. More recently, screening of a total of 1729 polymorphisms across the whole HLA region in several independent Caucasian T1D datasets, revealed evidence of a secondary peak of association for T1D independent of known DQB1 and DRB1 effects, due to the HLA-B locus (P combined = 2.01 x 10 -19 ) with the B*39 allele consistently associated with T1D and some evidence for an effect of B*18 [55].…”

Section: Evidence For Role Of Hla Class I In Diseasementioning

confidence: 88%

The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action

Gough

Simmonds²

2007

400

172

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Abstract:The HLA region encodes several molecules that play key roles in the immune system. Strong association between the HLA region and autoimmune disease (AID) has been established for over fifty years. Association of components of the HLA class II encoded HLA-DRB1-DQA1-DQB1 haplotype has been detected with several AIDs, including rheumatoid arthritis, type 1 diabetes and Graves' disease. Molecules encoded by this region play a key role in exogenous antigen presentation to CD4+ Th cells, indicating the importance of this pathway in AID initiation and progression. Although other components of the HLA class I and III regions have also been investigated for association with AID, apart from the association of HLA-B*27 with ankylosing spondylitis, it has been difficult to determine additional susceptibility loci independent of the strong linkage disequilibrium (LD) with the HLA class II genes. Recent advances in the statistical analysis of LD and the recruitment of large AID datasets have allowed investigation of the HLA class I and III regions to be re-visited. Association of the HLA class I region, independent of known HLA class II effects, has now been detected for several AIDs, including strong association of HLA-B with type 1 diabetes and HLA-C with multiple sclerosis and Graves' disease. These results provide further evidence of a possible role for bacterial or viral infection and CD8+ T cells in AID onset. The advances being made in determining the primary associations within the HLA region and AIDs will not only increase our understanding of the mechanisms behind disease pathogenesis but may also aid in the development of novel therapeutic targets in the future.

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“…Although such an interpretation may be the correct one at times, many other MHC genes deserve attention as alternative explanations for HLA associations. Some investigators have considered these non-HLA genes [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] and these efforts would be facilitated by better characterization of the relationships among these MHC genes.…”

Section: Introductionmentioning

confidence: 99%

Conserved extended haplotypes of the major histocompatibility complex: further characterization

et al. 2006

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Since the complete sequencing of a human major histocompatibility complex (MHC) haplotype, interest in non-human leucocyte antigen (HLA) genes encoded in the MHC has been growing. Non-HLA genes, which outnumber the HLA genes, may contribute to or account for HLA and disease associations. Most information on non-HLA genes has been obtained in separate studies of individual loci. To comprehensively address polymorphisms of relevant non-HLA genes in 'conserved extended haplotypes' (CEH), we investigated 101 International Histocompatibility Workshop reference cell lines and nine additional anonymous samples representing all 37 unambiguously characterized CEHs at MICA, NFKBIL1, LTA, NCR3, AIF1, HSPA1A, HSPA1B, BF, NOTCH4 and a single nucleotide polymorphism (SNP) at HLA-DQA1 as well as MICA, NOTCH4, HSPA1B and all five tumour necrosis factor short tandem repeat (STR) polymorphisms. This work (1) provides an extensive catalogue of MHC polymorphisms in all CEHs, (2) unravels interrelationships between HLA and non-HLA haplotypical lineages, (3) resolves reported typing ambiguities and (4) describes haplospecific markers for a number of CEHs. Analysis also identified a DQA1 SNP and segments containing MHC class III polymorphisms that corresponded with class II (DRB3 and DRB4) lineages. These results portray the MHC where lineages containing non-HLA and HLA variants in linkage disequilibrium may operate in concert and can guide more thorough design and interpretation of HLA-disease relationships.

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Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?

Cited by 12 publications

References 24 publications

Comparative immunogenetics of autism and schizophrenia

Comparative immunogenetics of autism and schizophrenia

The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action

Conserved extended haplotypes of the major histocompatibility complex: further characterization

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