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Am. J. Respir. Crit. Care Med., Volume 163, Number 6, May 2001, 1432-1436

Analysis of Tumor Necrosis Factor-alpha , Lymphotoxin-alpha , Tumor Necrosis Factor Receptor II, and Interleukin-6 Polymorphisms in Patients with Idiopathic Pulmonary Fibrosis

PANAGIOTIS PANTELIDIS, GREGORY C. FANNING, ATHOL U. WELLS, KENNETH I. WELSH, and ROLAND M. DU BOIS

Interstitial Lung Disease Unit, Department of Occupational and Environmental Medicine, Imperial College of Science, Technology and Medicine, National Heart and Lung Institute, & Royal Brompton and Harefield NHS Trust, London; and Oxford Tissue Typing Centre, Nuffield Department of Surgery, The Churchill Hospital, Oxford, United Kingdom

Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation that is associated with structural damage of the lung and fibrosis. Although the etiology of IPF is unknown, it is likely to involve an interaction between environmental and multiple genetic components. Animal models of pulmonary fibrosis have shown that proinflammatory mediators are critical at both the inflammatory and fibrotic stages of the disease. Genetic variants exist in genes encoding proinflammatory mediators, as well as in genes encoding their receptors, which makes these genes candidates for the pathogenesis of IPF. In the present study, we examined 12 biallelic polymorphisms in the genes for tumor necrosis factor (TNF)-alpha (+488[G/A], -238[G/A], -308[G/A]), lymphotoxin (LT)-alpha (+720[C/A], +365[C/G], and +249[A/G], determining haplotypes LT-alpha 1 to LT-alpha 4), tumor necrosis factor-receptor 2 (TNF-RII) (gb:M32315: 676[T/G], 1663[A/G], 1668[T/G], 1690[C/T]), and interleukin- (IL)-6 (promoter -174[G/C], intron 4[A/G]). We also examined the haplotypes determined by the three biallelic polymorphisms in each of the TNF-alpha and LT-alpha genes. As compared with a normal control population, the IPF group showed no significant deviations in genotype, allele, or haplotype frequencies. Surprisingly, in the IPF population, but not in the control population, an increased frequency of cocarriage of the IL-6 intron 4G and the TNF-RII 1690C alleles was observed, despite the location of the two genes on different chromosomes. Moreover, using impairment of carbon monoxide transfer (DLCO) adjusted for duration of dyspnea as a marker of rapidity of disease progression, we found that the IL-6 intron 4GG genotype was the only genotype independently associated with lower DLCO levels. These findings, if independently confirmed, will be the first to suggest that disease progression in IPF may be linked to a particular genetic marker or to functional polymorphisms in other genes near that marker.




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