VitGene International Consortium to Identify Susceptibility Genes for Generalized

描述（由申请人提供）：全身性白癜风是最常见的色素沉着障碍，皮肤和覆盖的头发出现白色斑块，是由相关区域的黑色素细胞自身免疫丧失引起的。此外，广泛性白癜风与许多其他自身免疫性疾病高度相关，无论是在患者还是在其近亲中。广泛性白癜风是一种复杂而异质性的病因，涉及遗传和环境因素。目前还不知道有什么环境诱因。然而，从病例对照或基于家族的研究中，一些基因产生了重复的（尽管不是完全一致的）关联或连锁不平衡（LD），并且使用多重家族的全基因组连锁研究已经提供了几个染色体区域参与全身性白癜风风险的证据。发现白癜风的潜在遗传成分是了解疾病发病机制的关键，其长期目标是开发抑制或重新调节自身免疫过程的新疗法，加强通过黑素细胞重新聚集刺激皮肤重新着色的治疗。该提案代表了一个国际合作联盟，“VitGene”，其中包括世界上大多数研究白癜风遗传学的领先研究人员，世界上大多数领先的白癜风临床小组，以及世界上最大的白癜风患者支持小组。我们共同积累了大量来自全身性白癜风患者的dna，以及许多有多例全身性白癜风的大家庭的dna。我们建议通过开展广泛性白癜风的全基因组关联研究（GWAS）来寻找致病基因，采用多阶段研究设计，利用可用的患者资料，最大限度地提高统计能力和效率，同时最大限度地降低成本。最初的全基因组发现阶段将在1500名白种人患者和1500名白种人对照中进行。随后的两个连续随访阶段将对选定的候选关联信号进行随访，首先在2,750名白种人病例和2,750名白种人对照中进行测试，然后对至少200名白种人多重家族和至少150名三联体进行基于家庭的关联分析。最后，在扩展阶段，在白种人中确认的关联信号将在来自许多不同的非白种人种族群体的病例对照队列中进行测试，包括美国西班牙裔/拉丁裔，哥伦比亚西班牙裔，非洲裔美国人/非洲裔加勒比人，巴基斯坦中东部，韩国和日本。因此，这将把分析扩展到与美国少数民族人口相关的来自世界各地的许多其他民族人口。公共卫生相关性：全身性白癜风是最常见的色素沉着障碍，黑色素细胞的自身免疫性死亡导致皮肤和头发出现白色斑块，患者患其他自身免疫性疾病的风险很高，如甲状腺疾病、成人1型糖尿病、类风湿性关节炎、狼疮等。广泛性白癜风涉及基因和环境因素。在这里，一个国际联盟，VitGene，提出了一项多阶段全基因组关联研究（GWAS），旨在发现控制广泛性白癜风易感性的基因，其长期目标是了解疾病发病机制，促进白癜风和其他自身免疫性疾病的新治疗方法的开发。

DESCRIPTION (provided by applicant): Generalized vitiligo is the most common pigmentation disorder, white patches of skin and overlying hair resulting from autoimmune loss of melanocytes from the involved areas. Moreover, generalized vitiligo is highly associated with a number of other autoimmune diseases, both in patients and in their close relatives. Generalized vitiligo has a complex and heterogeneous etiology, involving both genetic and environmental causal factors. No causal environmental triggers are yet known. However, several genes have yielded repeated, though not perfectly consistent, association or linkage disequilibrium (LD) from case-control or family-based studies, and genome-wide linkage studies using multiplex families have provided evidence for involvement of several chromosomal regions in risk of generalized vitiligo. Discovery of underlying genetic components of vitiligo is key to understanding disease pathogenesis, with the long-term goal of developing novel treatments that suppress or re-regulate the autoimmune process, enhancing treatments that stimulate skin re-pigmentation by melanocyte re-population. This proposal represents a collaborative international consortium, "VitGene", which includes most of the world's leading investigators studying the genetics of vitiligo, most of the world's leading vitiligo clinical groups, and the world's largest vitiligo patient support groups. Together, we have accumulated a large collection of DNAs from patients with generalized vitiligo, and many extended families with multiple cases of generalized vitiligo. We propose to search for causal genes by carrying out a genome-wide association study (GWAS) of generalized vitiligo, using a multi-stage study design that utilizes available patient material to maximize statistical power and efficiency while minimizing cost. An initial genome-wide discovery stage will be carried out in 1,500 Caucasian patients and 1,500 Caucasian controls. Two subsequent sequential followup stages will follow-up selected candidate association signals, first by testing in a second cohort of 2,750 Caucasian cases and 2,750 Caucasian controls, and then by family-based association analysis of at least 200 Caucasian multiplex families and at least 150 trios. Finally, in an extension stage, association signals confirmed in Caucasians will then be tested in case-control cohorts derived from a number of different non- Caucasian ethnic groups, including USA Hispanic/Latino, Columbian Hispanic, African-American/Afro- Caribbean, east-central Pakistani, South Korean, and Japanese. This will thus extend analyses to a number of other ethic populations from around the world that are relevant to minority populations in the USA. PUBLIC HEALTH RELEVANCE: Generalized vitiligo is the most common pigmentation disorder, autoimmune death of melanocytes resulting in white patches of skin and hair, and patients are at high risk of other autoimmune diseases such as thyroid disease, adult type 1 diabetes, rheumatoid arthritis, lupus, and others. Generalized vitiligo involves both genes and environmental triggers. Here, an international consortium, VitGene, proposes a multi-stage genome-wide association study (GWAS) aimed at discovering genes that control susceptibility to generalized vitiligo, with the long-term goal of understanding disease pathogenesis to facilitate developing novel treatments for vitiligo and perhaps other autoimmune diseases.