Investigation of Pulmonary Fibrosis Susceptibility Gene : from Silicosis Mouse to IIP and SIlicosis Patients

[小鼠模型]我们进行了全基因组连锁分析，以阐明小鼠肺纤维化的易感基因。我们在前期的研究中发现了矽尘暴露对小鼠肺反应的遗传影响，在8个品系的小鼠中，C57 BL/6 J（B6）是最敏感的品系，CBA/J（CBA）是抗性品系。为了鉴定与矽肺相关的基因，我们用B6和CBA进行了杂交（F2）。利用Map Manager QTX进行了数量性状基因座（QTL）的全基因组连锁分析。以羟脯氨酸作为肝纤维化指标，对167个标记基因进行基因型分析。对暴露于硅土的F2群体进行全基因组连锁分析，在第4染色体上发现了显著的QTL，在第3和第18染色体上分别发现了提示性QTL。[矽肺患者]为了解释个体对二氧化硅暴露的反应差异，我们假设TNF-α基因多态性可能与 关于我们 α或甘露糖结合凝集素（MBL）和肺对二氧化硅颗粒的反应。为了验证这一点，我们研究了TNF-α启动子多态性（-308，-238，-376）与结节性硅肺（n=84），进行性块状纤维化（PMF）（n=44）和健康对照（n=122）的相关性。结果显示，矽肺组-308A等位基因频率显著高于对照组（6.35%和2.05%），P<0.01。结节性硅肺组也明显高于PMF组（p<0.05）。这些结果表明，TNF-α-308A可能会增加结节性硅肺的易感性。我们还研究了在日本人群中常见的MBL密码子54与结节性病变（n=97）、PMF（n=48）和健康对照（n=84）的相关性。PMF组突变等位基因频率显著高于对照组（分别为19.80%、12.9%，p<0.05）。这些结果表明MBL密码子54突变等位基因可能促进矽肺PMF的发生。少

[Mouse Model] We have performed genome-wide linkage analysis to elucidate the susceptibility genes to pulmonary fibrosis in mice. From our previous study, we have found genetic contribution to pulmonary response to silica exposure, and that C57BL/6J (B6) was the most susceptible strain and CBA/J (CBA) was the resistant one among 8 strains of mice. In order to identify responsible genes in response to silicosis, we bred intercross (F2) between B6 and CBA. Agenome-wide linkage analysis of quantitative trait loci (QTLs) was performed using Map Manager QTX. As an index of fibrosis, hydroxyproline was applied, and genotypes of 167 marker genes were analyzed. A genome-wide linkage analysis of silica exposed F2 cohort identified significant QTL on chromosome 4 and suggestive QTLs on chromosomes 3 and 18 respectively.[Silicosis Patients] To explain individual variability in response to silica exposure, we have made our hypothesis that there might be an association between polymorphisms of TNF- … More alpha or mannose binding lectin (MBL) and lung response to silica particle. To examine this, we have studied the association of TNF-alpha promoter polymorphisms (-308, -238, -376) with nodular silicosis (n=84), and progressive massive fibrosis (PMF) (n=44), and healthy controls (n=122). Results showed that frequency of -308A allele frequency was significantly higher in silicosis compared to controls (6.35% and 2.05%, p<0.01). It was also significantly higher in patients with nodular silicosis compared to PMF (p<0.05). These results suggest that TNF-alpha-308A might enhance susceptibility to nodular silicosis. We also have studied the, association of MBL codon 54, which is common in Japanese population, with nodular lesion (n=97), PMF (n=48), and healthy controls (n=84). PMF group had significantly higher frequency of mutant allele than control group (19.80%, 12.9% respectively, p<0.05). These results suggest that MBL codon 54 mutant allele might enhance the development of PMF in silicosis. Less