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

Abstract

Fibrosing alveolitis (FA) is characterized by persistent inflammation and elevated production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), 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-alpha 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-1beta and/or excessive TNF-alpha may play a pathophysiologic role in this condition.

Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1β in idiopathic pulmonary fibrosis

“…However, a limitation of this study is that the number of IPF patients is relatively small for genetic associations. Conversely, the results are in line with previously published literature [6,28]. Although our data suggest no effect of age or gender on the IL-1Ra/ IL-1b ratio (results not shown), more studies are needed to confirm the role of a decreased ratio in IPF.…”

“…A predisposing effect of genetic variation in IL1RN was described previously by Whyte et al, who found an increased risk of fibrosing alveolitis in an Italian and a British population [6]. They investigated the IL1RN + 2018 SNP, which in the Caucasian Hapmap panel is in complete linkage disequilibrium with our tag rs408392 (r 2 = 1).…”

“…In other studies the variable number of tandem repeats (VNTR) in intron 2 of IL1RN was investigated and found to be in linkage disequilibrium with the IL1RN + 2018 SNP. However, both a small Australian [7] and an independent Czech cohort [12] 1·3 (0·5-3·8)* 0·2 (0·1-0·3) Eosinophils (¥10 6 ) 0·8 (0·4-2·7)* 0·03 (0·01-0·08) *P < 0·05 compared to healthy controls. IQR: interquartile range.…”

“…Polymorphisms in the IL-1 receptor antagonist gene (IL1RN) and TNF have been associated with susceptibility to IPF [6,7]. Several studies suggest that IL-1b and IL-1Ra play a critical role in bleomycin-induced fibrosis in mice.…”

The TNF−α –308, MCP−1 –2518 and TGF−β1 +915 polymorphisms are not associated with the development of chronic lung disease in very low birth weight infants

“…[9][10][11][12] The TNF À308 A allele has been associated with the development or increased severity of several lung diseases. [13][14][15] Transforming growth factor-b 1 (TGF-b 1 ), a multifunctional cytokine that regulates differentiation and proliferation of fibroblasts, is produced by many cell types in the lung. Increased expression of TGF-b 1 has been implicated in the development of lung fibrosis in both animal models and human disease.…”