TYPE I DIABETES AND GENES OF THE HLA-D REGION

I型(胰岛素依赖型)糖尿病(IDD)与 人类白细胞抗原区域的基因，特别是等位基因人类白细胞抗原-DR3和-DR4。然而， 只有一小部分携带这些等位基因的个体会患上IDD，所以 血清学定义的标记物并不是非常特异。这个 亚型的识别与IDD的相关性比 传统的DR血清型将提供具有更高特异性的标记 并提高我们对IDD易感性的遗传学的理解。 该提案的总体目标是通过以下方式定义人类白细胞抗原-DR亚型 DNA多态，为IDD的易感性提供了更好的标记。在……里面 综上所述，具体目标是：使用DNA探针检测人类白细胞抗原DR和DC 识别人类白细胞抗原-D限制性片段(RF)多态的基因 确定IDD患者RF和RF单倍型的频率 和对照；检验DR3和DR4的某些亚型的假设 与血清学类型本身相比，对IDD具有更强的特异性。 家庭研究将部分利用我们的大量资源 冻结的材料。人类白细胞抗原家族中的淋巴细胞已被储存 超过100个IDD的成员。这些单元将扩展为 白介素2，以产生足够的DNA用于分析。DNA也将是 来自对照家系和IDD和IDD的随机样本 对照，谁将是人类白细胞抗原分型。将通过与DNA杂交的方式研究DNA 人类白细胞抗原DR和DC探针，经限制性内切酶和 南方印迹。个人之间的射频差异将在 确认孟德尔人的种族隔离和与人类白细胞抗原的连锁。 DR类型的子类型将被检测为RF模式之间的差异 与单一灾难恢复类型相关联。这些亚型的识别将 提高人类白细胞抗原相关标记物的特异性和分辨率 IDD。更好的标记将使易感人群有更准确的定义 最终将有助于在DNA水平上识别基因 对IDD的易感性。

Type I (Insulin-dependent) diabetes (IDD) is significantly associated with genes of the HLA region, especially the alleles HLA-DR3 and -DR4. However, only a small proportion of individuals with these alleles develop IDD, so the serologically defined markers are not very specific. The identification of subtypes more strongly associated with IDD than are the conventional DR serotypes would provide markers with increased specificity and improve our understanding of the genetics of susceptibility to IDD. The overall goal of this proposal is to define HLA-DR subtypes by means of DNA polymorphisms and provide better markers for susceptibility to IDD. In summary, the specific aims are: to use DNA probes for the HLA-DR and DC genes to identify restriction fragment (RF) polymorphisms in the HLA-D region; to determine the frequencies of the RF's and RF haplotypes in IDD's and controls; to test the hypothesis that certain subtypes of DR3 and DR4 have greater specificity for IDD than do the serological types themselves. Family studies will be carried out in part using our large resource of frozen material. Lymphocytes have been stored from HLA-typed family members of more than 100 IDD's. These cells will be expanded with Interleukin-2, to yield sufficient DNA for analysis. DNA will also be obtained from control families, and from random samples of IDD's and controls, who will be HLA-typed. DNA will be studied by hybridization with HLA-DR and DC probes, after digestion with restriction endonucleases and Southern blotting. RF differences between individuals will be studied in families to confirm Mendelian segregation and linkage with HLA. Subtypes of DR types will be detected as differences among RF patterns associated with a single DR type. Identification of such subtypes will increase both the specificity and the resolution of HLA-linked markers for IDD. Better markers will allow a more precise definition of susceptible individuals and will ultimately help identify, at the DNA level, the genes for susceptibility to IDD.