Am. J. Respir. Crit. Care Med., Volume 165, Number 8, April 2002, 1119-1124

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

Jan C. Grutters, Hiroe Sato, Panagiotis Pantelidis, Anna L. Lagan, Deirdre S. McGrath, Jan-Willem J. Lammers, Jules M. M. van den Bosch, Athol U. Wells, Roland M. du Bois, and Kenneth I. Welsh

Heart Lung Center Utrecht, Department of Pulmonology, Sint Antonius Hospital, Nieuwegein, the Netherlands; Clinical Genomics Group, Department of Occupational and Environmental Medicine, Imperial College of Science, Technology, and Medicine, National Heart and Lung Institute, London, United Kingdom; and Heart Lung Center Utrecht, Department of Pulmonology, University Medical Center, Utrecht, the Netherlands

Interindividual variation in the expression of tumor necrosis factor (TNF)- 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.

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