Study On Association Of Tumor Necrosis Factor-α And Interleukin-1 Receptor Antagonist (RA) Gene Polymorphisms With Silicosis

Objective: It is researched recently that some cytokines gene polymorphisms have close relationship with the susceptibility of silicosis.Cytokines gene polymorphisms influences the occurrenc and the severity of silicosis through inducing differences of the quantity of cytokines produced caused by effecting its transcription,and also cause individual difference of silicosis. Tumor necrosis factor- α (TNF- α ) and interleukin-1 (IL-1) are the two cytokines that have been researched more at present, which play important roles in progressive fibrosis and respiratory tract inflammation induced by silic dust,and its gene polymorphisms influence the quantity of cytokines produced and the severity of silicosis. The aims of this research is to study the distribution of TNF-α , IL-1RA(one of subtypes of IL-1) gene polymorphisms among Chinese patients of silicosis,and to approach whether polymorphisms within TNF- α and IL-IRA gene promoter region are associated with susceptibility to silicosis in southwest Chinese Han population, so as to give an important genetic background toexplain the function of TNF- α, IL-IRA gene polymorphisms in the development of silicosis and in order to protect the health of susceptible population for silicosis.Objects and Methods: 75 cases of silicosis and 137 silica-exposed workers(being employed) were selected as subjects from a certain Iron and Steel Group Corporation in southwest China by randomized cluster sampling. All subjects were male , who had experience of silicon-exposure , similar working experience , exposed to similar dust environment , no blood relationship with each other,no disease of immune system and other severe disease. Posterior and anterior chest X-rays were taken for each subject, and then were diagnosed by a group of experts according to the "National Diagnosis Criterion about silicosis" (GBZ70-2002) .The cases of silicosis were divided into three subgroups based on the various stages of Ⅰ, Ⅱ ,Ⅲ. 5ml peripheral vein blood was drawn from each subject. By means of polymerase chain reaction-restriction fragment length polymorphisms(PCR-RFLP) techniques, the DNA of all subjects was typed for G-to-A transitions at positions -308 and -238 of TNF-α gene ,and its polymorphisms were analyzed;But IL-IRA gene polymorphisms was analyzed by real-time quantitative polymerase chain reaction techniques.Results: Our study showed that the frequency of TNF α -308A among the cases with silicosis was higher than that among the silica-exposed workers (controls) (22.0% versus 12.8%, Fisher's exact p value < 0.01); The frequency of allelic A was just a little higher in cases with phase I silicosis (13.6%) than in controls, which statistic difference being not sigmficant(P>0.01),but the frequency of allelic A was much higher in cases with phase II and Ⅲ silicosis(33.9%) than in controls(P < 0.01).The same phenomenon applied to TNF α -238A(10.0% versus 1.1%, Fisher's exact p value < 0.01).After adjusted for educational background, economic status, smoking history, drinking history, ABO blood type and years of exposure to silicon dust, the -308A was still associated with the presence of silicosis (for silicosis phase I: adjusted OR=1.37, 95%CI=0.57~3.29, p>0.01; for silicosis phase II and III: adjusted OR= 5.59, 95%CI=2.08~ 15.05, P<0.01); and the -238A was also associated with the presence of silicosis (for silicosis phaseⅠ: adjusted OR=17.48, 95%CI=4.66~ 920.51, P <0.01; for silicosis phase Ⅱ and Ⅲ: adjusted OR= 22.25, 95%CI=5.27~995.81, P<0.01).Our study showed that the frequency of IL-1RA+2018C among the cases with silicosis was higher than that among the silica-exposed workers (controls) (28.0% versus 15.0%, Fisher's exact p value < 0.01 ); The frequency of allelic C was higher incases with phase Ⅰ silicosis than in controls(31.8% versus 15.0%, Fisher's exact p value < 0.01 ); The frequency of allelic C was higher in cases with phase Ⅱ and Ⅲ silicosis than in controls,but which statistic difference being not significant(22.6% versus 15.0%, Fisher's exact p value >0.01). After adjusted for confounding factors, the frequency of IL-1RA+2018C among silicoses and its subgroups was still higher than among controls, which statistic difference being significant(Fisher's exact p value < 0.01).Conclusions: ① In southwest Chinese han population,the frequencies of TNF-a-308A and TNF-α-238A respectively are 22.0%,10.0% among cases with silicosis, and 12.8% and 1.1% among silica-exposed workers.②The variants in TNF-α-308( G→A) influences the occurrence of phase Ⅱ and Ⅲ silicosiss significantly,but not does for phase I silicosiss.This indicates that TNF-α polymorphism at position -308(G→A) may influence the extent and the severity of silicosis.③In southwest Chinese han population,the frequencies of IL-IRA +2018C respectively are 28.0% among cases with silicosis and 15.0% among silica-exposed workers. ④IL-1RA gene polymorphisms played an important role inmaking the Han population of southwest China susceptible to silicosis. IL-IRA may be taked as a gene to be selected for studing the Susceptibility of silicosis.