VitGene International Consortium to Identify Susceptibility Genes for Generalized

描述（由申请人提供）： 泛发性白癜风是最常见的色素沉着疾病，黑色素细胞的自身免疫性死亡导致皮肤和毛发的白色斑块，并且患者处于其他自身免疫性疾病如甲状腺疾病、成人1型糖尿病、类风湿性关节炎、狼疮等的高风险中。泛发性白癜风是一种“复杂性状”，涉及多个基因和环境触发因素。母基金，AR 0056292，VitGene国际联盟确定泛发性白癜风易感基因，资助国际联盟全基因组关联研究（GWAS），旨在发现控制泛发性白癜风易感性的基因。这一竞争性修订，提交的回应FRA NOT-OD-09-079，“NIH宣布恢复法案资金的竞争性修订申请的可用性”，扩大了母基金的范围，仍然在其第一年，通过增加立即详细的重新测序和后续关联研究的目的，我们已经发现的泛发性白癜风易感基因，NALP 1（NLRP 1），目的是发现导致疾病的特定DNA序列变异。这些研究的长期目标是提高对疾病发病机制的理解，以促进开发白癜风和其他自身免疫性疾病的新疗法。这个竞争性修订项目将能够雇用更多的工作人员和增加目前兼职实验室工作人员的工作时间。 NLRP 1编码NALP 1（NACHT-LRR蛋白1），这是先天免疫系统的关键调节因子，可能参与启动自身免疫过程。在这次竞争性修订中，我们建议在第1年进行NLRP 1的高通量DNA序列分析，在NLRP 1区域重新测序~175 kb（《第十七次人权报告》：5，340，000 - 5，515，000;在815个个体中构建36.1），包括相同的114个美国/英国CEU多发性白癜风家族和相同的罗马尼亚CEU病例-对照组中，我们以前确定，并随后确认与NLRP 1 SNP的遗传关联。随后，在第1年和第2年，我们将对通过重新测序鉴定的泛发性白癜风和NLRP 1变异体进行基于家族和病例对照的遗传关联分析。这将首先在114个CEU多发性白癜风家族和罗马尼亚CEU病例对照队列中进行测序，以确定最可能代表疾病致病变异的变异。随后将在1500例不相关的CEU病例和1300例CEU对照中独立检测这些特异性变异与泛发性白癜风的相关性，这些病例和对照是在父母资助的泛发性白癜风GWAS背景下收集的，1 R 01 AR 056292。总之，这些研究将确定NLRP 1中的致病变异，然后可以通过功能分析进行随访。 公共卫生相关性：泛发性白癜风是最常见的色素沉着疾病，黑色素细胞的自身免疫性死亡导致皮肤和毛发的白色斑块，并且患者处于其他自身免疫性疾病如甲状腺疾病、成人1型糖尿病、类风湿性关节炎、狼疮等的高风险中。泛发性白癜风涉及基因和环境触发器。母基金，AR 0056292，VitGene国际联盟确定泛发性白癜风易感基因，资助了一项国际联盟全基因组关联研究（GWAS），旨在发现控制泛发性白癜风易感性的基因。这个竞争性修订通过增加我们已经发现的广义白癜风易感基因NLRP 1的详细研究的目的，以发现导致疾病的特定DNA序列变异，扩大了该资助的范围。这些研究的长期目标是提高对疾病发病机制的理解，以促进开发白癜风和其他自身免疫性疾病的新疗法。

DESCRIPTION (provided by applicant): 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 is a "complex trait", involving both multiple genes and environmental triggers. The parent grant, AR0056292, VitGene International Consortium to Identify Susceptibility Genes for Generalized Vitiligo, funds an international consortium genomewide association study (GWAS) aimed at discovering genes that control susceptibility to generalized vitiligo. This Competitive Revision, submitted in response to FRA NOT-OD-09-079, "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications", expands the scope of the parent grant, still in its first year, by adding the Aim of immediate detailed re-sequencing and follow-up association studies of a generalized vitiligo susceptibility gene we have already discovered, NALP1 (NLRP1), with the goal of discovering specific DNA sequence variations that cause disease. The long-term goal of these studies is to improve understanding of disease pathogenesis to facilitate developing novel treatments for vitiligo and perhaps other autoimmune diseases. This Competitive Revision project will enable hiring of additional staff and increasing hours of current part-time laboratory staff. NLRP1 encodes NALP1 (NACHT-LRR protein 1), a key regulator of the innate immune system that is likely involved in initiation of the autoimmune process. In this Competitive Revision, we propose to carry out high-throughput DNA sequence analysis of NLRP1 in year 1, re-sequencing ~175 kb across the NLRP1 region (chr17:5,340,000-5,515,000; Build 36.1) in 815 individuals, comprising the same 114 USA/UK CEU multiplex vitiligo families and the same Romanian CEU case-control cohort in which we previously identified and subsequently confirmed genetic association with NLRP1 SNPs, respectively. Subsequently, in years 1 and 2, we will carry out family-based and case-control genetic association analyses of generalized vitiligo and NLRP1 variants identified by re-sequencing. This will first be done in the 114 CEU multiplex vitiligo families and Romanian CEU case-control cohort that were sequenced, so as to identify those variants that most likely represent disease-causal variants. These specific variants will subsequently be independently tested for association with generalized vitiligo in 1500 unrelated CEU cases and 1300 CEU controls collected in the context of the generalized vitiligo GWAS supported by the parent grant, 1R01AR056292. Together, these studies will identify disease-causal variants in NLRP1 that can then be followed up by functional analyses. 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. The parent grant, AR0056292, VitGene International Consortium to Identify Susceptibility Genes for Generalized Vitiligo, funds an international consortium genome-wide association study (GWAS) aimed at discovering genes that control susceptibility to generalized vitiligo. This Competitive Revision expands the scope of this grant by adding the Aim of detailed studies of a generalized vitiligo susceptibility gene we have already discovered, NLRP1, with the goal of discovering specific DNA sequence variations that cause disease. The long-term goal of these studies is improve understanding of disease pathogenesis to facilitate developing novel treatments for vitiligo and perhaps other autoimmune diseases.