Am. J. Respir. Crit. Care Med., Volume 162, Number 2, August 2000, 755-758

Increased Risk of Fibrosing Alveolitis Associated with Interleukin-1 Receptor Antagonist and Tumor Necrosis Factor- Gene Polymorphisms

MOIRA WHYTE, RICHARD HUBBARD, RICCARDO MELICONI, MICHELLE WHIDBORNE, VANESSA EATON, COLIN BINGLE, JANINE TIMMS, GORDON DUFF, ANDREA FACCHINI, ANGELA PACILLI, MARIO FABBRI, IAN HALL, JOHN BRITTON, IAN JOHNSTON, and FRANCESCO DI GIOVINE

Division of Molecular and Genetic Medicine, University of Sheffield, Sheffield, and Department of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom; and Policlinico S. Orsola and Istituti Ortopedici Rizzoli, University of Bologna, Bologna, Italy

Fibrosing alveolitis (FA) is characterized by persistent inflammation and elevated production of tumor necrosis factor-alpha (TNF-), interleukin-1 beta (IL-1), and interleukin-1 receptor antagonist (IL-1ra) in the lung. Single base variations at position +2018 in the IL-1ra gene (IL-1RN) and position -308 in the TNF- gene (TNF-A) are overrepresented in other chronic inflammatory disease populations. We have tested the hypothesis that predisposition to FA may also be influenced by these polymorphisms by genotyping 88 cases and matched controls from England and 61 cases and 103 unmatched controls from Italy. The rarer allele for IL-1RN and TNF-A was designated allele 2 in each case. For IL-1RN allele 2, in the English group, the relative odds of FA were increased in homozygous subjects by an odds ratio (OR) of 10.2 (95% confidence intervals [CI], 1.26 to 81.4; p = 0.03) and for carriers by an OR of 1.85 (95% CI, 0.94 to 3.63; p = 0.075). In the Italian population, the risk of FA was increased, in IL-1RN allele 2 homozygotes (OR, 2.54; 95% CI, 0.68 to 9.50; p = 0.2) and in carriers (OR 2.40; 95% CI, 1.26 to 4.60; p = 0.008). Carriage of TNF-A allele 2 was also associated with increased risk of FA in the English (OR, 1.85; 95% CI, 0.94 to 3.63; p = 0.075) and Italian (OR, 2.50; 95% CI, 1.14 to 5.47; p = 0.022) populations. These data suggest IL-1RN (+2018) allele 2 and TNF-A (-308) allele 2 confer increased risk of developing FA and, therefore, that unopposed IL-1 and/or excessive TNF- may play a pathophysiologic role in this condition.

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