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来阐明小鼠肺纤维化的易感基因。通过前期研究，我们发现肺对二氧化硅暴露的反应与遗传有关，8株小鼠中C57BL/6J （B6）最敏感，CBA/J （CBA）最耐药。为了确定对矽肺反应负责的基因，我们在B6和CBA之间进行了杂交（F2）。使用Map Manager QTX进行全基因组数量性状位点（QTLs）连锁分析。采用羟脯氨酸作为纤维化指标，分析167个标记基因的基因型。对暴露于二氧化硅的F2群体进行全基因组连锁分析，发现4号染色体上有显著性QTL， 3号染色体和18号染色体上分别有提示性QTL。[矽肺病患者]为了解释个体对二氧化硅暴露的反应差异，我们提出了我们的假设，即TNF-…More α或甘露糖结合凝集素（MBL）多态性与肺部对二氧化硅颗粒的反应之间可能存在关联。为了检验这一点，我们研究了tnf - α启动子多态性（-308,-238,-376）与结节性矽肺病（n=84）、进行性大规模纤维化（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<0.01）。结节性矽肺患者与PMF患者相比也显著增高（p<0.05）。这些结果提示tnf - 308a可能增加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与结节性病变（n=97）、PMF （n=48）和健康对照（n=84）的关系。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）。这些结果提示MBL密码子54突变等位基因可能促进矽肺PMF的发展。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