Comprehensive Genome Interrogation of African American Sarcoidosis Families

描述（由申请人提供）：结节病的特征是导致多器官肉芽肿形成的超免疫反应。它对非裔美国人的影响比白人更频繁，也更严重。虽然先前的连锁、混合、候选基因和全基因组关联（GWA）研究显示了统计学上令人信服的影响，但因果变异仍然未知，许多结节病的遗传性尚未得到解释。这种“缺失”的遗传力可能包括常见（次要等位基因频率（MAF）低于5%）和罕见变异（MAF<5%）的影响，因为在aa中，前者没有得到充分的代表，后者则完全没有被商业基因分型阵列所探索。这些事实，再加上下一代测序的可用性，迫使我们对形成结节病基础的遗传变异进行详尽的搜索。在本项目中，我们将整合大量平行的人类外显子组和靶向测序数据，以及之前收集的AA结节病家族的基因型和表型数据，以识别未发现的遗传变异。我们广泛的，独一无二的样品将最大限度地检测RV关联并帮助建立阶段，这对于理解变异的分子生理学至关重要。我们将1)通过外显子组测序鉴定编码区变异，2)通过靶向重测序捕获先前研究发现的39个区域编码和非编码序列中的变异，3)在独立样本中重复真阳性CV和RV效应。我们的团队领导了在AAs中寻找结节病基因的工作，并在肺病学，遗传学，流行病学，基因组测序，生物统计学和生物信息学方面拥有专业知识，我们是世界上唯一一个完全准备好成功完成计划项目的团队。所产生的数据肯定会确定候选的因果变异，为功能研究提供基础见解，并导致重要的炎症新假设，从而不仅对结节病而且对其他炎症疾病也有新的治疗方法。

DESCRIPTION (provided by applicant): Sarcoidosis is characterized by a hyperimmune response resulting in granuloma formation in multiple organs. It affects African Americans (AAs) more frequently and more severely than whites. While previous linkage, admixture, candidate gene and genome-wide association (GWA) studies show statistically compelling effects, causal variants are still unknown and much of sarcoidosis heritability is yet to be explained. This "missing" heritability likely includes effects of both common (minor allele frequency (MAF)>5%) and rare variants (MAF<5%), since, in AAs, the former are inadequately represented and the latter are completely unexplored by commercial genotyping arrays. These facts, coupled with the availability of next-generation sequencing compel us to perform an exhaustive search for genetic variants that form the basis of sarcoidosis. For this proposal, we will integrate massivel parallel human exome and targeted sequencing data with previously collected genotype and phenotype data in AA sarcoidosis families to identify undiscovered genetic variants. Our extensive, one-of-a-kind sample will maximize power to detect RV association and help to establish phase, which is critical in understanding the molecular physiology of variants. We will 1) identify coding region variants by exome sequencing, 2) capture variants in the coding and noncoding sequence of 39 regions identified by previous studies via targeted resequencing, and 3) replicate, in an independent sample, true positive CV and RV effects. Our assembled team has led the search for sarcoidosis genes in AAs, and with expertise in pulmonology, genetics, epidemiology, genome sequencing, biostatistics and bioinformatics, we are the only group in the world perfectly poised to successfully complete the proposed projects. The data generated are certain to identify candidate causal variants, provide fundamental insight for functional studies and lead to important new hypotheses of inflammation resulting in new treatments in not only sarcoidosis but other inflammatory diseases as well.