Increased Frequency of the Uncommon Tumor Necrosis Factor -857T Allele in British and Dutch Patients with Sarcoidosis

Interindividual variation in the expression of tumor necrosis factor (TNF)-alpha suggests the existence of functionally distinct TNF alleles, which might play a role in sarcoidosis. We investigated five potentially functional biallelic TNF promoter polymorphisms at nucleotide positions -1,031(T/C),...

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Published in:American journal of respiratory and critical care medicine 2002-04, Vol.165 (8), p.1119-1124
Main Authors: Grutters, Jan C, Sato, Hiroe, Pantelidis, Panagiotis, Lagan, Anna L, McGrath, Deirdre S, Lammers, Jan-Willem J, van den Bosch, Jules M. M, Wells, Athol U, du Bois, Roland M, Welsh, Kenneth I
Format: Article
Language:English
Subjects:
Biological and medical sciences
Gene Frequency
Genotype
Haplotypes
Humans
Medical sciences
Netherlands
Phenotype
Point Mutation
Polymerase Chain Reaction
Polymorphism, Genetic
Promoter Regions, Genetic - genetics
Sarcoidosis, Pulmonary - genetics
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Tumor Necrosis Factor-alpha - genetics
United Kingdom
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Summary:Interindividual variation in the expression of tumor necrosis factor (TNF)-alpha suggests the existence of functionally distinct TNF alleles, which might play a role in sarcoidosis. We investigated five potentially functional biallelic TNF promoter polymorphisms at nucleotide positions -1,031(T/C), -863(C/A), -857(C/T), -307(G/A), and -237(G/A) in two clinically well-defined groups of white patients (British [UK] and Dutch [NL]) with sarcoidosis, each with their own control subjects. Polymorphisms were determined using SSP-PCR. A total of 772 individuals were studied (96 UK patients, 354 UK control subjects, 100 NL patients, 222 NL controls). A significant increase in the rarer TNF -857T allele was found in both sarcoidosis populations. In total 25.5% of the sarcoid patients carried the TNF -857T allele versus 14.1% of the control subjects (p = 0.003, p(c) = 0.02). In the sarcoidosis group the allele frequency of this polymorphism was 13.5% versus 7.3% in the control subjects (p = 0.0003, p(c) = 0.002). Subgroup analysis showed a significant increase in the rarer TNF -307A (TNF-2) allele in patients with Löfgren's syndrome (p = 0.006, p(c) = 0.03). Our finding does not necessarily imply that the two polymorphisms relate to different functions; it may be that one or both are in linkage disequilibrium with the causal site. This requires further studies of functionality and linkage disequilibrium.
ISSN:1073-449X
1535-4970
DOI:10.1164/ajrccm.165.8.200110-0320