MAPPING OF VITILIGO SUSCEPTIBILITY GENES

白癜风易感基因图谱

• 批准号: 6778719
• 负责人: RICHARD ANDREW SPRITZ
• 金额: $ 54.5万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6778719
• 关键词: British Isles; United States; autoimmune disorder; caucasian American; clinical research; comorbidity; disease /disorder onset; family genetics; gene frequency; genetic mapping; genetic markers; genetic susceptibility; genotype; human genetic material tag; human subject; linkage mapping; questionnaires; vitiligo

DESCRIPTION (provided by applicant): Generalized vitiligo is an autoimmune disorder characterized by acquired white patches of skin and overlying hair due to loss of melanocytes from these areas. Depigmentation is progressive and disfiguring, often resulting in significant psychological trauma. Vitiligo is the most common disorder of pigmentation, with frequency of approximately 0.5% in most populations. Family clustering of cases is not uncommon, in a non-Mendelian pattern suggestive of multifactorial, polygenic inheritance involving both genetic and non-genetic factors. Furthermore, in about half of families vitiligo is associated with autoimmune thyroid disease, pernicious anemia, Addison's disease, lupus, and perhaps inflammatory bowel disease, in both probands and their relatives, indicating that these autoimmune diseases share common etiologic factors, most likely genetic. During the current grant period we surveyed two vitiligo patient groups, the Vitiligo Society (UK) and the National Vitiligo Foundation (USA), ascertaining > 3300 probands, and we subsequently collected and genotyped DNA samples from 94 multiplex Caucasian vitiligo families from this group. By genome-wide genetic linkage analyses, we detected a number of putative linkage signals genome-wide, 3 of which meet genomewide criteria for ' significant' linkage; one of these (AIS1, on 1p) has now been confirmed, showing dominant linkage in larger, autoimmunity-associated vitiligo families. To confirm some of these linkage signals, and to detect others, we now propose to collect and genotype samples from a replicate cohort of 33 larger amd 61 smaller Caucasian families. Confirmed linkage signals will be fine-mapped to determine which can be more finely resolved and linkage signal strength improved. A major aim is the identification of AIS1 by classic positional cloning utilizing large AIS1-linked families. We have already tested a number of genes in the AIS1 interval, and have found potential variants in the FOXD3 promoter that will be now tested for their effect on FOXD3 transcription. Additional patients will be searched for mutations in FOXD3 and in other genes if FOXD3 appears to not be AIS1. A final, related aim to identify one or more additional vitiligo susceptibility genes, depending on linkage results obtained. The long-term significance of this work may be to develop specific approaches to disease therapy and prevention and to apply those modalities to patients at high genetic risk.

描述（由申请人提供）： 广义白癜风是一种自身免疫性疾病，其特征是由于这些区域的黑素细胞损失而导致皮肤的白色斑块和上覆盖的头发。脱位是渐进的和毁容的，通常会导致重大的心理创伤。白癜风是最常见的色素沉着障碍，大多数人群的频率约为0.5％。病例的家庭聚类并不少见，在非孟德尔模式中，暗示了涉及遗传因素和非遗传因素的多因素，多基因遗传。此外，在大约一半的家庭中，白癜风与概率及其亲戚的自身免疫性甲状腺疾病，恶性贫血，艾迪生氏病，狼疮以及可能的炎症性肠病有关，这表明这些自身免疫性疾病具有共同的病因学因素，最可能具有遗传性。 在当前的赠款期间，我们调查了两个白癜风患者组，即白紫色协会（UK）和国家Vitiligo基金会（美国），确定> 3300个概率，随后我们从该组中收集并从94个多重性高核性白化病系列中收集并进行了基因分型DNA样品。通过全基因组遗传链接分析，我们检测到许多推定的连锁信号，其中3个符合“重要”连接的基因组标准。现在已经确认了其中一个（AIS1，1P），显示出较大的自身免疫相关的白癜风家族中的主要联系。 为了确认其中一些连锁信号并检测其他链接信号，我们现在建议从33个较大的AMD 61个较小的高加索家庭中收集和基因型样品。确认的链接信号将被细化，以确定哪些可以更精细解决，并提高连锁信号强度。 一个主要目的是通过使用大型AIS1连接家庭的经典位置克隆来识别AIS1。我们已经在AIS1间隔中测试了许多基因，并发现了FOXD3启动子中的潜在变体，该变体现在将测试其对FOXD3转录的影响。如果FOXD3似乎不是AIS1，则将在FOXD3和其他基因中搜索其他患者。最终的相关目的是根据获得的连锁结果确定一个或多个额外的白癜风敏感性基因。 这项工作的长期意义可能是开发特定的疾病治疗和预防方法，并将这些方式应用于具有高遗传风险的患者。