title: Increased frequency of the uncommon tumor necrosis factor -857T allele in British and Dutch patients with sarcoidosis.
abstract: 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.
authors.affiliation: Heart Lung Center Utrecht, Department of Pulmonology, Sint Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Grutters
authors.forename: Hiroe
authors.initials: H
authors.lastname: Sato
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Pantelidis
authors.forename: Anna L
authors.initials: AL
authors.lastname: Lagan
authors.forename: Deirdre S
authors.initials: DS
authors.lastname: McGrath
authors.forename: Jan-Willem J
authors.initials: JW
authors.lastname: Lammers
authors.forename: Jules M M
authors.initials: JM
authors.lastname: van den Bosch
authors.forename: Athol U
authors.initials: AU
authors.lastname: Wells
authors.forename: Roland M
authors.initials: RM
authors.lastname: du Bois
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Welsh
mesh_terms: D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D009426:Netherlands; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D017565:Sarcoidosis, Pulmonary / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D006113:United Kingdom
chemical_list: D014409:Tumor Necrosis Factor-alpha