Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms

Fibrosing alveolitis (FA) is characterized by persistent inflammation and e levated production of tumor necrosis factor-alpha (TNF-alpha), interleukin- 1 beta (IL-1 beta), and interleukin-1 receptor antagonist (IL-1ra) in the l ung. Single base variations at position +2018 in the IL-1ra gene (IL-1RN) a nd position -308 in the TNF-alpha gene (TNF-A) are overrepresented in other chronic inflammatory disease populations. We have tested the hypothesis th at predisposition to FA may also be influenced by these polymorphisms by ge notyping 88 cases and matched controls from England and 61 cases and 103 un matched controls from Italy. The rarer allele for IL-1RN and TNF-A was desi gnated allele 2 in each case. For IL-1RN allele 2, in the English group, th e relative odds of FA were increased in homozygous subjects by an odds rati o (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 Ita lian population, the risk of FA was increased, in IL-1RN allele 2 homozygot es (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 associate d 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) populat ions. These data suggest IL-1RN (+2018) allele 2 and TN F-A (-308) allele 2 confer increased risk of developing FA and, therefore, that unopposed IL-1 beta and/or excessive TNF-alpha may play a pathophysiologic role in this c ondition.