HLA CLASS II POLYMORPHISMS AND AUTOIMMUNE DISEASE IN AFRICAN AMERICANS

该项目的长期目标是确定 HLA与胰岛素依赖型糖尿病易感性的相关性研究 （胰岛素依赖型糖尿病）和自身免疫型白癜风（ATV），并确定关系 非裔美国人和非裔美国人之间的HLA基因型频率差异 白种人与人群间胰岛素依赖型糖尿病发病率的差异。 的 在非洲，疾病关联中的HLA变异性分析得到加强 美国人，因为在这一人群中发现的HLA多态性程度更高， 人口 聚合酶链反应技术及与 序列特异性寡核苷酸探针将用于定义HLA-DR， 非裔美国人胰岛素依赖型糖尿病和ATV患者的DQ等位基因 study. 还将确定家庭成员以确定HLA 单倍型。 我们假设易感性之间的结构同源性 等位基因和保护性等位基因和/或单倍型。 具体目标是 定义DRB 1、DRB 3、DRB 4、DRB 5、DQA 1和QB 1等位基因和单倍型， 患者和对照组;确定每个这些等位基因的频率 分析DQA 1 Arg 52的顺反剂量效应， DQB 1 Asp 57等位基因在胰岛素依赖型糖尿病患者和正常人中的分布及对胰岛素依赖型糖尿病的评估 华盛顿，华盛顿特区非裔美国人的基因型特异性发病率 DR 4等位基因高变区序列同源性与发病年龄的关系 将分析ATV中发病年龄较晚的DR 6和DR 6等位基因 并与胰岛素依赖型糖尿病的DR 4等位基因进行比较。 此外，易受 和保护性等位基因/单倍型，重点是 DRB 1 *0302、DQB 1 *0402、DQA 1 *0401在非裔美国人中的独特多态性， 将相对于与疾病异质性的相关性进行评价。 这 项目重点是HLA II类基因组多态性的定义 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HLA多态性将用于评估 DQA 1、DQB 1和DRB等位基因在胰岛素依赖型糖尿病易感性中的相对作用 还有ATV。 HLA-DR和DQ等位基因的分子特征及 DNA水平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，并且可能在 更好地理解免疫遗传因素在 IDDM和ATV的发病机制。 此外，新的信息产生于 疾病易感性模体可能对基因设计具有指导意义 这些类型的自身免疫性疾病的治疗方法。

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.