VitGene International Consortium to Identify Susceptibility Genes for Generalized

描述(申请人提供)：泛发性白癜风是最常见的色素沉着障碍，皮肤上的白色斑块和覆盖的毛发是由受累区域的黑素细胞自身免疫损失引起的。此外，泛发性白癜风与许多其他自身免疫性疾病高度相关，无论是在患者身上还是在他们的近亲中。泛发性白癜风的病因复杂多样，既涉及遗传因素，也涉及环境因素。目前尚不清楚致病的环境因素。然而，在病例对照或基于家庭的研究中，几个基因产生了重复的关联或连锁不平衡(LD)，尽管不是完全一致的，而且使用多重家族的全基因组连锁研究提供了几个染色体区域参与泛发性白癜风风险的证据。发现白癜风潜在的遗传成分是了解疾病发病机制的关键，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繁殖刺激皮肤重新色素沉着的疗法。这项提议代表了一个名为“Vitgene”的国际协作性联盟，该联盟包括研究白癜风遗传学的大多数世界领先的研究人员、世界上大多数领先的白癜风临床团体，以及世界上最大的白癜风患者支持团体。总而言之，我们收集了大量泛发性白癜风患者的DNA，以及许多有多个泛发性白癜风病例的大家庭。我们建议通过对泛发性白癜风进行全基因组关联研究来寻找致病基因，采用多阶段研究设计，利用现有的患者材料最大化统计能力和效率，同时最小化成本。最初的全基因组发现阶段将在1500名高加索患者和1500名高加索人对照中进行。随后的两个后续阶段将跟踪选定的候选关联信号，首先通过在2750名高加索病例和2750名高加索对照的第二个队列中进行测试，然后通过对至少200个高加索多胎家庭和至少150个三联体进行基于家庭的关联分析。最后，在推广阶段，在高加索人中确认的关联信号将在病例对照队列中进行测试，这些队列来自一些不同的非高加索族群，包括美国西班牙裔/拉丁裔、哥伦比亚拉美裔、非裔美国人/非洲加勒比人、巴基斯坦中东部、韩国和日本人。因此，这将把分析扩展到来自世界各地的与美国少数族裔人口相关的其他一些民族人口。公共卫生相关性：泛发性白癜风是最常见的色素沉着障碍，是黑素细胞的自身免疫性死亡，导致皮肤和头发形成白色斑块，患者患有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。泛发性白癜风既涉及基因，也涉及环境因素。在这里，国际联盟Vitgene提出了一项多阶段全基因组关联研究(Gwas)，旨在发现控制泛发性白癜风易感性的基因，长期目标是了解疾病的发病机制，以促进开发新的白癜风和其他自身免疫性疾病的治疗方法。

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.