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，在8个品系的小鼠中，C57BL/6J(B6)是最敏感的品系，CBA/J(CBA)是抗性品系。为了找出与矽肺相关的基因，我们用B6和CBA杂交(F2)。利用MAP Manager QTX进行全基因组数量性状基因座(QTL)连锁分析。以羟脯氨酸作为肝纤维化指标，对167个标志物基因进行基因分型。对接触二氧化硅的F2人群进行的全基因组连锁分析发现，在第4染色体上有显著的QTL，在第3和第18染色体上有提示的QTL。[矽肺患者]为了解释接触二氧化硅的个体差异，我们假设肿瘤坏死因子-…的多态之间可能存在关联。更多的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，我们研究了肿瘤坏死因子-α启动子(-308、-238、-376)多态性与结节状矽肺(n=84)、进行性大块纤维化(PMF)(n=44)和健康对照(n=122)的关系。结果显示，矽肺患者-308A等位基因频率显著高于对照组(6.35%和2.05%，p&lt；0.01)。与PMF相比，结节状矽肺患者也显著升高(p&lt；0.05)。这些结果提示，肿瘤坏死因子-α-308a可能增加了结节性矽肺的易感性。我们还研究了日本人群中常见的MBL密码子54与结节病变(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&lt；0.05)。提示MBL密码子54突变等位基因可能促进矽肺PMF的发生。较少

[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