Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosisfactor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammatio n that is associated with structural damage of the lung and fibrosis. Altho ugh the etiology of IPF is unknown, it is likely to involve an interaction between environmental and multiple genetic components. Animal models of pul monary fibrosis have shown that proinflammatory mediators are critical at b oth the inflammatory and fibrotic stages of the disease. Genetic variants e xist in genes encoding proinflammatory mediators, as well as in genes encod ing their receptors, which makes these genes candidates for the pathogenesi s of IPF. In the present study, we examined 12 biallelic polymorphisms in t he 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], determi ning haplotypes LT-alpha1 to LT-alpha4), tumor necrosis factor-receptor 2 ( TNF-RII) (gb:M32315: 676[T/G], 1663[A/G], 1668[T/G], 1690[C/T]), and interl eukin-(IL)-6 (promoter -174[G/C], intron 4[A/G]). We also examined the hapl otypes determined by the three biallelic polymorphisms in each of the TNF-a lpha and LT-alpha genes. As compared with a normal control population, the IPF group showed no significant deviations in genotype, allele, or haplotyp e 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 gen es 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 on ly genotype independently associated with lower DLCO levels. These findings , if independently confirmed, will be the first to suggest that disease pro gression in IPF may be linked to a particular genetic marker or to function al polymorphisms in other genes near that marker.