Comprehensive Genome Interrogation of African American Sarcoidosis Families

描述（由申请方提供）：结节病的特征是导致多个器官肉芽肿形成的超免疫反应。它影响非洲裔美国人（AAs）比白人更频繁，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，但因果变异仍是未知的，许多结节病遗传性尚待解释。这种“缺失的”遗传可能包括常见（次要等位基因频率（MAF）>5%）和罕见变异（MAF<5%）的影响，因为在AA中，前者的代表性不足，后者完全没有被商业基因分型阵列探索。这些事实，再加上下一代测序的可用性，迫使我们对构成结节病基础的遗传变异进行详尽的搜索。 对于这项提议，我们将整合平行的人类外显子组和靶向测序数据与先前收集的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、独一无二的样本将最大限度地提高检测RV相关性的能力，并有助于建立阶段，这对于理解变体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体，2）通过靶向重测序捕获先前研究鉴定的39个区域的编码和非编码序列中的变体，3）在独立样本中复制真阳性CV和RV效应。 我们的团队领导了对AA中结节病基因的研究，并拥有肺病学，遗传学，流行病学，基因组测序，生物统计学和生物信息学的专业知识，我们是世界上唯一一个完全准备好成功完成拟议项目的团队。所产生的数据肯定会识别候选的因果变异，为功能研究提供基本的见解，并导致重要的炎症新假设，不仅导致结节病的新治疗方法，还导致其他炎症性疾病。

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.