Genetic studies of vitiligo

白癜风的遗传学研究

• 批准号: 8900951
• 负责人: RICHARD ANDREW SPRITZ
• 金额: $ 70.68万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-11 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900951
• 关键词: Accounting; Affect; Architecture; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; Biological Markers; Biology; Budgets; Candidate Disease Gene; Classification; Clinical; Color; Comorbidity; Data; Data Set; Development; Disease; Employee Strikes; European; Exhibits; Extramural Activities; Family; Genes; Genetic; Genetic study; Genotype; Goals; Grant; HLA-A gene; Hair; Health; Heritability; Individual; International; Joints; Knowledge; Learning; Maps; Medical; Meta-Analysis; Mining; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Pathogenesis; Pathway interactions; Patients; Penetrance; Persons; Phenotype; Population; Prevention; Regenerative Medicine; Relative (related person); Risk; Skin; Social isolation; Stem cells; Stress; Susceptibility Gene; Testing; Translating; Variant; Vitiligo; base; clinical epidemiology; cost; database of Genotypes and Phenotypes; disease phenotype; feeding; functional genomics; genetic analysis; genetic epidemiology; genetic pedigree; genetic risk factor; genetic variant; genome wide association study; genome-wide; genome-wide linkage; improved; innovation; melanocyte; novel; novel strategies; proband; segregation; skin patch; transmission process

DESCRIPTION (provided by applicant): This is a resubmitted renewal proposal to continue genetic studies of generalized vitiligo (GV), a common autoimmune disease in which white patches of skin and hair result from destruction of melanocytes. Striking skin depigmentation in GV particularly impacts persons of color, with frequent social isolation and psychiatric co- morbidity. In addition, GV patients have ~30% risk of developing other autoimmune diseases, resulting in direct medical co-morbidity. Our genetic studies of GV began 15 years ago with basic studies of genetic and clinical epidemiology, followed by candidate gene association studies and genomewide linkage studies. During the past grant period we organized the International VitGene Consortium to perform two highly successful GWAS in European-derived whites (EUR), as well as studies of other populations, identifying ~32 GV susceptibility genes and defining novel pathobiological pathways. Beyond the GWAS, we have gone on to NextGen re-sequencing of most of the genes detected by the first GWAS, identifying common (and some uncommon/rare) causal variants in HLA-A, TYR, NLRP1, and GZMB. Potential causal variants identified in to date, as well as those identified in this proposal, are carried forward to functioal analysis in our parallel project, "Functional Analysis of Vitiligo Genes" (AR045584). Our findings provide the basis of the first theoretical biological framework for vitiligo autoimmune pathogenesis, and have translated directly to improved patient classification and improved treatment. Nevertheless, known GV loci account for only ~18% of GV heritability (h2), and most causal gene variants remain unknown. Statistical genetic analysis of our combined GV GWAS datasets shows that considerable "hidden" h2 for GV resides in the remaining data, which can be mined at relatively low cost. Our goals are thus to augment the GV "parts list" of genes and pathways, identify causal variants, relate GV genetic and allelic architecture to clinical sub-phenotypes and disease biomarkers, and understand causal functional biology. A strong rationale to discover additional GV loci is that we do not yet know enough biology to control melanocyte-directed autoimmunity. If this could be achieved, GV would be one of the best AI disease candidates for regenerative medicine, since the skin melanocyte (or melanocyte stem cell) reservoir remains intact. Here, we thus propose to: 1) carry out a small third EUR GWAS to mine additional GV loci, powered to OR ~1.2 (probably the practical limit of GWAS); 2) fine-map GV loci to identify specific genes and define common and some uncommon causal variants; followed by two innovative Aims, to 3) identify potential uncommon/rare causal variants by analyses of multiplex GV families; and 4) relate the genetic architecture of GV to specific clinical and biomarker sub-phenotypes and test whether the same GV loci/variants also cause a related phenotype, segmental vitiligo (SV). It is our goal that the resultant biological knowledge will provide the basis for new approaches to treatment and even prevention of GV and associated autoimmune diseases.

描述（由申请人提供）：这是一项重新提交的更新提案，旨在继续广泛性白癜风（GV）的遗传学研究，这是一种常见的自身免疫性疾病，皮肤和头发上出现白色斑块是由于黑色素细胞遭到破坏而导致的。 GV 中显着的皮肤色素脱失尤其影响有色人种，经常出现社会孤立和精神共病。此外，GV 患者有约 30% 的风险患上其他自身免疫性疾病，从而导致直接的医疗共病。 我们对GV的遗传学研究始于15年前，首先是遗传学和临床流行病学的基础研究，随后是候选基因关联研究和全基因组连锁研究。在过去的资助期内，我们组织了国际 VitGene 联盟，在欧洲白人 (EUR) 中进行了两次非常成功的 GWAS，并对其他人群进行了研究，确定了约 32 个 GV 易感基因并定义了新的病理生物学途径。除了 GWAS 之外，我们还对第一个 GWAS 检测到的大多数基因进行了 NextGen 重新测序，识别了 HLA-A、TYR、NLRP1 和 GZMB 中常见（和一些不常见/罕见）的因果变异。迄今为止确定的潜在因果变异以及本提案中确定的变异将在我们的平行项目“白癜风基因功能分析”(AR045584) 中进行功能分析。 我们的发现 为白癜风自身免疫发病机制提供了第一个理论生物学框架的基础，并直接转化为改善患者分类和改善治疗。然而，已知的 GV 位点仅占 GV 遗传力 (h2) 的约 18%，并且大多数致病基因变异仍然未知。对我们组合的 GV GWAS 数据集进行的统计遗传分析表明，剩余数据中存在大量 GV 的“隐藏”h2，这些数据可以以相对较低的成本进行挖掘。 因此，我们的目标是扩充基因和通路的 GV“部分列表”，识别因果变异，将 GV 遗传和等位基因结构与临床亚表型和疾病生物标志物联系起来，并了解因果功能生物学。发现额外 GV 基因座的一个强有力的理由是我们还没有足够的生物学知识来控制黑素细胞定向的自身免疫。如果能够实现这一点，GV 将成为再生医学的最佳人工智能疾病候选者之一，因为皮肤黑素细胞（或黑素细胞干细胞）库保持完整。 因此，在这里，我们建议：1）进行第三次 EUR GWAS 来挖掘额外的 GV 位点，OR ~1.2（可能是 GWAS 的实际极限）； 2) 精细绘制 GV 位点以识别特定基因并定义常见和一些不常见的因果变异；其次是两个创新目标，3) 通过分析多重 GV 家族来识别潜在的不常见/罕见的因果变异； 4) 将 GV 的遗传结构与特定的临床和生物标志物亚表型联系起来，并测试相同的 GV 基因座/变异是否也会引起相关的表型，即节段性白癜风 (SV)。我们的目标是由此产生的生物学知识将为治疗甚至预防 GV 和相关自身免疫性疾病的新方法提供基础。