AFFECTED SIBPAIR & DISEQUILIBRIUM MAPPING OF IDDM GENES

胰岛素依赖型糖尿病易感基因的鉴定 糖尿病（IDDM）将提供：1）重要的新信息， 疾病的发病机理和2）用于识别 可能受益于保护性治疗的个体， 正在接受调查在此，我们建议继续我们的 旨在确定与胰岛素依赖型糖尿病有关的易感基因的研究， 自身免疫性疾病，其中产生胰岛素的胰腺β细胞 都被摧毁了我们已经分析了104个受影响的同胞对（ASP） 家族，并确定了5个与胰岛素依赖型糖尿病相关的基因组间隔， 除了长期公认的IDDM 1（HLA）和IDDM 2（INS区域）之外。IDDM3 已被映射到15 q26，IDDM 4到11 q13，IDDM 5到6 q24，IDDM 7到2 q31- 问题33。其他研究者也报告了这些间期。我们 第一组将IDDM 8定位到6 q25-q27上的21 cM基因组区域。在 此外，有证据表明， 其他10个基因组区域。由于胰岛素依赖型糖尿病是遗传异质性的， 受环境影响，大多数联系仍然需要 在额外的数据集确认。因此，我们将利用我们独特的 我们的电脑网络的胰岛素依赖型糖尿病家庭扩大150，我们的好 建立ASP家族的集合。然后我们将使用我们的新 确定的家庭设置，以确定所有假定的连锁区间。如在 过去，我们的新家庭将提供给其他感兴趣的 在人类生物学数据的支持下， 交换（HBDI）。在HLA复合体之外， IDDM 8（MLS =3.4）及其对疾病的影响（MLS = 1.8）是 在我们的数据集中确定的所有易感性区间中最强。 因此，我们建议对这一连锁区间进行精细定位。 在500个家庭的ASP分析将首先用于缩小IDDM 8 间隔在3 scM内。连锁不平衡分析将是 使用ASP和单纯家族以及无关患者进行 和来自不同种族的对照人群（高加索人、中国人 非裔美国人）。非均衡分析的最终目的是 以检测标记-疾病关联并确定基因组区域， 这与疾病有很大关系。候选基因 遗传间隔值得特别注意。在IDDM 8间隔内， 已鉴定出2个这样的基因座，SOD 2和IGF 2 R。我们的初步 观察结果表明，与IDDM 8有关的证据是一致的， 与基因组印记，一个模式类似，已经报道的 IGF2R。具有挑衅性的是，一个父亲印记的基因负责β 暂时性新生儿糖尿病的细胞功能障碍也被认为是 定位在6号染色体上 这份提案将提供重要信息 通过定位克隆最终鉴定IDDM基因 技术.

Identification of genes that confer susceptibility to insulin-dependent diabetes mellitus (IDDM) will provide: 1) important new information about the pathogenesis of the disease and 2) a means for identifying individuals who may benefit from the protective therapies that are currently under investigation. Herein, we propose a continuation of our studies aimed at identifying susceptibility genes involved in IDDM, an autoimmune disease in which the insulin-producing, pancreatic beta cells are destroyed. We have already analyzed 104 affected sibpair (ASP) families and identified 5 genomic intervals that are linked to IDDM, in addition to the long recognized IDDM1 (HLA) and IDDM2 (INS region). IDDM3 has been mapped to 15q26, IDDM4 to 11q13, IDDM5 to 6q24, IDDM7 to 2q31- q33. These intervals were also reported by other investigators. We were the first group to map IDDM8 to a 21cM genomic region on 6q25-q27. In addition, suggestive evidence of linkage has been reported for more than 10 other genomic regions. Since IDDM is genetically heterogeneous and subject to environmental influences, most of the linkages still require confirmation in additional data sets. Thus, we will exploit our unique computerized network of IDDM families to expand by 150, our well established collection of ASP families. We will then use our newly ascertained family set to confirm all putative linkage intervals. As in the past, our new families will be made available to other interested investigators worldwide under the auspices of the human biological data interchange (HBDI). Outside of the HLA complex, the evidence of linkage for IDDM8 (MLS =3.4) and its impact on disease (lambdas = 1.8) are the strongest among all susceptibility intervals identified in our data set. We therefore propose to carry out fine mapping for this linkage interval. ASP analysis in 500 families will first be used to narrow the IDDM8 interval within 3-ScM. Linkage disequilibrium analysis will then be performed using the ASP and simplex families as well as unrelated patient and control populations from diverse ethnic groups (Caucasians, Chinese and African Americans). The ultimate goal of disequilibrium analysis is to detect marker-disease association and to define the genomic region that is significantly associated with the disease. Candidate genes within a genetic interval merit special attention. Within the IDDM8 interval, 2 such loci have been identified, SOD2 and IGF2R. Our preliminary observations indicate that the linkage evidence for IDDM8 is consistent with genomic imprinting, a pattern similar to that already reported for IGF2R. Provocatively, a paternally-imprinted gene responsible for beta cell disfunction in transient neonatal diabetes mellitus has also been mapped to chromosome 6. This proposal will provide important information for the ultimate identification of IDDM genes by positional cloning techniques.