Genomic imprinting and instability in IDDM

在高加索人群中的关联研究显示，与Hardy-Weinberg平衡中的比值相比，1型糖尿病（orIDDM）中化合物DQB1^<**>0302/^<**>0201的过量是一致的。这种遗传复杂性强烈表明，表观遗传和合子后事件可能参与这种多因素疾病的发病机制。为了阐明IDDM1基因的基因组印迹作用，本项目对27个自身免疫介导的1型糖尿病后代进行了单倍型遗传连锁不平衡（TDT）检测。我们发现，在日本人群中，高易感等位基因DQA1^<**>0301-DQB1^<**>0302与自身免疫介导的1型糖尿病有关，而不是单倍型的种族变异。我们还发现，易感等位基因会优先从母亲遗传给后代，而不是从父亲遗传给后代。这一发现支持了IDDM1通过表观遗传机制参与1型糖尿病发病机制的假设。接下来，我们试图分离在IDDM和健康对照之间胰岛B细胞中表达的差异基因。为此，我们从同一个体的人胰岛素瘤及其周围胰腺组织中提取总细胞RNA。以胰岛素的特异性引物为对照，采用RT-PCR技术从RNA样品中扩增胰岛素cDNA。然后用3‘锚定引物逆转录RNA，用3’锚定引物和标记5'任意引物进行RT-PCR。电泳鉴定的条带模式研究了几种在胰腺B细胞中表达的ESTs，并与正常胰腺组织相比，可以检测出哪些ESTs是B细胞特异性的。这些结果将为根据IDDM的发病机制鉴定B细胞中基因的差异表达提供重要的数据库。少

Association studies in Caucasian in Caucasian populations have revealed that excess of compound DQB1^<**>0302/^<**>0201 in type 1 diabetes, orIDDM,is consistently observed compared to the ratio in Hardy-Weinberg's equilibrium. This genetic complixity strongly suggests that epigenetic and postzygotic events could be involved in the pathogenesis of this multifactorial disorder.In order to elucidate of genomic imprinting might be involved at IDDM1, in this project, test for ^<**>transmission linkage disequilibrium (TDT) of haplotypes according to the parent-of-origin among twenty-seven informative families of the autoimmune-mediated type 1 diabetic offspring were performed. We found that the highly susceptible allele DQA1^<**>0301-DQB1^<**>0302 is associated with autoimmune-mediated type 1 diabetes also in Japanese population in stead of ethnic variations of haplotypes. We also found that the susceptible allele would be preferentially transmitted from mothers but not from fathers to the a … More ffected offspring. This finding supports the hypothesis that the IDDM1 is involved in the pathogenesis of type 1 diabetes by an epigenetic mechanism.We next attempted to isolate genes that are expressed in B cells of pancreatic islets differentially between IDDM and healthy controls. For this purpose, we extracted total cellular RNA from human inslinoma and its surrounding pancreatic tissues from the same individuals. Insulin cDNA could be amplified from the RNA samples by RT-PCR using its specific primers as a control. We then reverse-transcribed the RNA with 3'anchor primer, and performed RT-PCR by 3'anchor primer and labeled 5'arbitrary primer. The patterns of identified bands in electrophoresis investigated several ESTs that expressed in the pancreatic B cells and could be detected what ESTs were B-cell specific when compared to that of normal pancreatic tissue. These results should represent an important database for the identification of differential expression of genes in B cells in according to the pathogenesis of IDDM. Less