Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man.

Awdeh, Zuheir L.; Raum, Donald; Yunis, Edmond J.; Alper, Chester A.

doi:10.1073/pnas.80.1.259

Cited by 322 publications

(164 citation statements)

References 27 publications

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“…For some individuals of Northern European descent, DR3 is in linkage disequilibrium with A1-Cw7-B8-TNFB*1-C2C-Bfs-C4AQ0-C4B1-DRB1*0301-DQA1* 0501-DQB1*0201. 52 Additionally, this is closely related to the previously described haplotype in some Northern and Western Europeans consisting of HLA-A1-B8-Cw7-DR3-DRq52a-DQ2.1 53,54 , which uses the older nomenclature. Mixtures of other alleles have been found to be in linkage disequilibrium at HLA within various European and African populations.…”

Section: Hla Antigenssupporting

confidence: 52%

The genetics of systemic lupus erythematosus: putting the pieces together

2002

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Section: Hla Antigenssupporting

confidence: 52%

The genetics of systemic lupus erythematosus: putting the pieces together

2002

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“…Given the high degree of linkage disequilibrium within the MHC, 32,33 it remains controversial whether the À308 TNF polymorphism is causal. By using reporter gene constructs to compare the transcriptional activity of TNF À308 promoter alleles in vitro, many studies have sought to examine the consequences of this SNP on TNF expression independently of HLA associations.…”

Section: Discussionmentioning

confidence: 99%

A critical assessment of the factors affecting reporter gene assays for promoter SNP function: a reassessment of −308 TNF polymorphism function using a novel integrated reporter system

et al. 2009

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One of the greatest challenges facing genetics is the development of strategies to identify functionally relevant genetic variation. The most common test of function is the reporter gene assay, in which allelic regulatory regions are used to drive the expression of a reporter gene, and differences in expression in a cell line after transient transfection are taken to be a reflection of the polymorphism. Many studies have reported small differences in single nucleotide polymorphism (SNP)-specific reporter activity, including the tumor necrosis factor (TNF) GÀ308A polymorphism. However, we have established that many variables inherent in the reporter gene approach can account for the reported allelic differences. Variables, such as the amount of DNA used in transfection, the amount of transfection control vector used, the method of transfection, the growth history of the host cells, and the quality and purity of DNA used, all influence TNF À308 SNP-specific transient reporter gene assays and serve as a caution for those researchers who apply this method to the functional assessment of polymorphic promoter sequences. We have developed an integrated reporter system that obviates some of these problems and shows that the TNF GÀ308A polymorphism is functionally relevant in this improved assay, thus confirming that the À308A allele expresses at a higher level compared with the À308G allele.

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“…This will be particularly difficult to distinguish for what have been termed ªancestralº or ªex-tendedº HLA haplotypes such as the very conserved A1, B8, DR3, DQ2 haplotype [68,69,70].…”

Section: Mechanisms Of Diabetogenicity Of Hla Moleculesmentioning

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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Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man.

Cited by 322 publications

References 27 publications

The genetics of systemic lupus erythematosus: putting the pieces together

The genetics of systemic lupus erythematosus: putting the pieces together

A critical assessment of the factors affecting reporter gene assays for promoter SNP function: a reassessment of −308 TNF polymorphism function using a novel integrated reporter system

Genetic control of autoimmunity in Type I diabetes and associated disorders

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