HLA CLASS II POLYMORPHISMS AND AUTOIMMUNE DISEASE IN AFRICAN AMERICANS

该项目的长期目标是确定 人类白细胞抗原与胰岛素依赖型糖尿病易感性的关系 (IDDM)与自身免疫型白癜风(ATV)的关系 非裔美国人和非裔美国人之间的人类白细胞抗原基因频率差异 高加索人对IDDM发病率的人群差异。这个 人类白细胞抗原在非洲疾病关联中的变异性分析得到加强 美国人因为在这种情况下发现了更大程度的人类白细胞抗原多态 人口。聚合酶链式反应技术及其与DNA的杂交 序列特异性寡核苷酸探针将用于定义人类白细胞抗原DR和 非洲裔美国人IDDM和ATV患者DQ等位基因的病例对照研究 学习。家庭成员也将被确定以确定人类白细胞抗原 单倍型。我们假设易感性之间的结构同源性 等位基因和保护等位基因和/或单倍型。具体目标是 定义DRB1、DRB3、DRB4、DRB5、DQA1和QB1等位基因和单倍型 患者和对照；确定每个等位基因的频率 分析DQA1、Arg52、DQA1、Arg52、DQA1Arg52、DQA1Arg52的顺反剂量效应 DQB1 Asp57等位基因在IDDM患者和对照组中的分布及IDDM的估计 华盛顿特区非裔美国人的基因特异性发病率。 DR4基因高变区序列同源性的早期发病 和DR6晚发年龄的易感等位基因将被分析 并与糖尿病患者的DR4易感等位基因S进行比较。此外，易受影响 和保护性等位基因/单倍型，重点是 DRB1*0302，DQB1*0402，DQA1*0401在非裔美国人中的独特多态性， 将根据与疾病异质性的关联进行评估。这 该项目的重点是定义人类白细胞抗原II类的基因组多态性 已知与自身免疫性疾病易感性相关的基因。 非裔美国人独特的人类白细胞抗原基因多态性将被用来评估 DQA1、DQB1和DRB等位基因对IDDM易感性的相对影响 和亚视。人类白细胞抗原DR和DQ等位基因的分子特征及 DNA水平上的单倍型将完善疾病的定义- 相关的等位基因和/或序列基序，可能在 更好地理解免疫遗传因素在糖尿病发病中的意义 IDDM和ATV的发病机制。此外，新的信息产生于 疾病易感基序可能对基因设计有指导意义 治疗这些类型的自身免疫性疾病的方法。

The long term objective of this project is to identify the genomic basis of HLA association with susceptibility to insulin dependent diabetes mellitus (IDDM) and auto-immune-type vitiligo (ATV) and determine the relationship of HLA genotype frequency differences between African Americans and Caucasians to population differences in the incidence of IDDM. The analysis of HLA variability in disease association is enhanced in African Americans because of the greater degree of HLA polymorphisms found in this population. The polymerase chain reaction technique and hybridization with sequence specific oligonucleotide probes will be used to define HLA- DR and DQ alleles in Africa-American patients with IDDM and ATV in a case-control study. Family members will also be ascertained to determine HLA haplotypes. We hypothesize structural homologies among susceptibility alleles and protective alleles and/or haplotypes. The specific aims are to define DRB1, DRB3, DRB4, DRB5, DQA1, and QB1 alleles and haplotypes in patients and controls; determine the frequency of alleles at each of these loci in IDDM and ATV; analyze the cis-trans-dose effect of DQA1 Arg52 and DQB1 Asp57 alleles in IDDM patients and controls, and estimate the IDDM genotype specific incidence for African Americans in Washington, D.C. Allelic hypervariable region sequence homology of DR4 early age of onset and DR6 late age of onset susceptibility alleles in ATV will be analyzed and compared with DR4 susceptibility allele(s) in IDDM. Also, susceptible and protective alleles/haplotypes, with a focus on the DRB1*0302,DQB1*0402,DQA1*0401 unique polymorphism in African Americans, will be evaluated relative to association with disease heterogeneity. This project focuses on the definition of genomic polymorphisms in HLA class II genes known to be associated with susceptibility to autoimmune disease. Unique HLA polymorphisms in African Americans will be used to assess the relative effect of DQA1, DQB1, and DRB alleles in susceptibility to IDDM and ATV. The molecular characterization of HLA-DR and DQ alleles and haplotypes at the DNA level will refine the definition of disease- associated alleles and/or sequence motifs and may be of great importance in better understanding the significance of immunogenetic factors in the pathogenesis of IDDM and ATV. Moreover, new information generated on diseases susceptibility motifs may be instructive in the design of gene therapy approaches to these types of autoimmune diseases.