Some disease-associated ancestral haplotypes carry a polymorphism of TNF

Dawkins, Roger L.; Leaver, Anne; Cameron, Paul; Martin, E.; Kay, Peter; Christiansen, Frank

doi:10.1016/0198-8859(89)90094-3

Cited by 73 publications

(36 citation statements)

References 14 publications

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“…24,37,67 This apparent association of SNPs results from the linkage of the TNFp*002 (À308A) allele with the LTAp*007 ( þ 253G, þ 724A) allele in several haplotypes, including the 8.1 ancestral haplotype (A1, B8, DR3). However, this association only holds from the perspective of the TNF À308A SNP, as it is not possible to type for either of the LTA SNPs and assume linkage.…”

Section: Discussionmentioning

confidence: 99%

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Novel polymorphisms and the definition of promoter ‘alleles’ of the tumor necrosis factor and lymphotoxin α loci: inclusion in HLA haplotypes

2003

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Tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) influence a variety of cellular responses and play a complex role in the immune response. Several single nucleotide polymorphisms (SNPs) have been reported in these major histocompatibility complex (MHC)-linked loci; however, a comprehensive examination of polymorphisms in the promoter regions of TNF and LTA has not been carried out and was undertaken here. Seven novel SNPs in LTA were identified by sequence analysis of 69 samples. Eight novel TNF alleles and 16 novel LTA alleles were designated. The TNF alleles clustered into two closely related groups, while the LTA alleles clustered into three distinct groups using phylogenetic and percentage difference analyses. A total of 52 unique TNF-LTA-HLA haplotypes are reported. There appear to be some associations between TNF/LTA alleles and HLA haplotypes, but not with specific HLA alleles. The majority of the SNPs appear to be randomly associated within and between the two loci except for the LTA SNPs at À293, þ 81 and þ 369. These observations may provide an explanation for the oftentimes contradictory results of studies associating individual cytokine gene SNPs with expression level phenotypes, HLA and disease.

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Section: Discussionmentioning

confidence: 99%

“…21 Several SNPs also have been reported in the introns 18 and a G/T dimorphism is present in the 3 0 UTR. 10,22 Nine SNPs have been reported in the LTA locus [23][24][25][26][27][28] ( Figure 1c). Three are located in the promoter region upstream of the transcription start site at À626 (G/A), À294 (C/T) and À293 (G/A).…”

Section: Introductionmentioning

confidence: 99%

Novel polymorphisms and the definition of promoter ‘alleles’ of the tumor necrosis factor and lymphotoxin α loci: inclusion in HLA haplotypes

2003

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“…The TNF probe should be specific for TNFa under the present conditions but it is not yet known how much different AHs vary with respect to TNF sequence and organization . Recently we have shown that the same TNFa probe can distinguish between AHs with or without a Nco I site within TNF0 (27) and there may be far more sequence polymorphism ofthe TNF gene family than previously appreciated (Du et al, manuscript in preparation) . Furthermore, some AHs contain hybrid C4 and DRB genes and it is possible that a similar phenomenon occurs elsewhere within the MHC, possibly including hybrids between different TNF genes.…”

Section: Resultsmentioning

confidence: 98%

“…These observations may relate to the present results since HLA DR2 and DR3 are carried by AHs 7.1, 8.1, and 18.2, respectively, and these three AHs have less TNF signal than 57 .1 and 62 .1 carrying HLA DR7 and DR4, respectively. The 8.1 AH is particularly interesting because it contains a C4 null (8,33), a polymorphism of TNF at the RFLP level (27), and as shown here, reduced gene copy numbers of C4, Cyp21, DRB, and possibly TNF. Any or all of these characteristics could be relevant to its association with autoimmune diseases such as SLE.…”

Section: Resultsmentioning

confidence: 99%

“…The 2 .1-kb Barn HI probe for Cyp21 (pC21/3c) was kindly provided by Dr. P. White (24) and has been shown to react with Cyp21A and B (2,3,21,25). The 0.8-kb Eco RI TNFa probe, which contains the entire coding region of mature TNF, was kindly provided by Dr. H. M. Shepard (26; Genentech Inc., South San Francisco, CA) and has been fully characterized (27,28). There is no detectable hybridization ofthis probe with TNF beta contained within genomic clones of 8.1 or 57 .1 (Du et al, manuscript in preparation).…”

Section: Methodsmentioning

confidence: 99%

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Differences in gene copy number carried by different MHC ancestral haplotypes. Quantitation after physical separation of haplotypes by pulsed field gel electrophoresis.

Zhang

Degli-Esposti

Cobain

et al. 1990

The Journal of Experimental Medicine

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We have examined the hypothesis that MHC ancestral haplotypes have a specific content of genes regulating the extent of autoimmune reactions. Gene copy number was quantitated by objective densitometry after PFGE was used to separate heterozygous AHs of different lengths. Initially we analyzed examples of known gene copy number at the C4 and 21 hydroxylase loci and showed that the approach provides predictable results. We then studied heterozygotes containing one characterized and one uncharacterized AH with particular attention to the gene copy number at the C4, Cyp21, and DRB loci. Each AH studied has a characteristic gene copy number at each locus studied. The same may be true of TNF, but other possibilities must be considered. AHs are markers for extensive chromosomal segments including particular numbers of several functional genes. Since AHs mark susceptibility to autoimmune disease, differences in gene copy number may be implicated.

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Comparative studies of the major histocompatibility complex in french canadian and non–french canadian caucasians with systemic lupus erythematosus

Goldstein

Sengar

1993

Arthritis & Rheumatism

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Objective. To investigate and compare the predisposing role of major histocompatibility complex (MHC) genes in systemic lupus erythematosus (SLE) in French Canadian and non-French Canadian (mainly AngloSaxon descent) Caucasian subjects.Methods. HLA-A, B, C (serology), DR, and DQ (restriction fragment length polymorphism [RFLP] typing) were determined. RFLP defining a large C4A,21-OHA deletion (Tuq I C4) and an Nco I tumor necrosis factor a (TNFa) RFLP were analyzed in 91 Caucasian Canadians and 91 ethnically matched control subjects.Results. In the total SLE and non-French Canadian SLE populations, HLA-B8, DR3(DR17), Dw24, DQ2, and the C4A gene deletion were associated with SLE. These HLA specificities and the C4A gene deletion were not significantly increased in French Canadian SLE patients compared with ethnically matched controls. When present in French Canadians, the C4A gene deletion was less closely associated with HLA-DR3(DR17), Dw24, DQ2 than in other Caucasians. HLA-DQ6 was associated with SLE in French Canadians. No association of the 2-allele Nco I TNFa RFLP with SLE was found in this population, in either ethnic group.Conclusion. These results support the importance of ethnic background in the study of MHC genes and SLE. The extended HLA-B8,DR3,C4A null haplotype is found mainly in SLE patients of Anglo-Saxon descent, while the DQ6 specificity is associated with SLE in French Canadians. This relatively genetically homogeneous Caucasian population offers the opportunity to study non-HLA-B8,DR3-4inked MHC influence in SLE.

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Some disease-associated ancestral haplotypes carry a polymorphism of TNF

Cited by 73 publications

References 14 publications

Novel polymorphisms and the definition of promoter ‘alleles’ of the tumor necrosis factor and lymphotoxin α loci: inclusion in HLA haplotypes

Novel polymorphisms and the definition of promoter ‘alleles’ of the tumor necrosis factor and lymphotoxin α loci: inclusion in HLA haplotypes

Differences in gene copy number carried by different MHC ancestral haplotypes. Quantitation after physical separation of haplotypes by pulsed field gel electrophoresis.

Comparative studies of the major histocompatibility complex in french canadian and non–french canadian caucasians with systemic lupus erythematosus

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