Comprehensive Genome Interrogation of African American Sarcoidosis Families

描述(申请人提供)：结节病的特征是高免疫反应导致多个器官的肉芽肿形成。它对非裔美国人(AA)的影响比白人更频繁、更严重。虽然以前的连锁、混合、候选基因和全基因组关联(GWA)研究显示了统计上令人信服的效果，但因果变异仍然未知，结节病的大部分遗传性仍未得到解释。这种“缺失”的遗传率可能包括常见的(次要等位基因频率(MAF)和5%)和罕见的变异(MAF&lt；5%)的影响，因为在AAS中，前者没有得到充分的表现，而后者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基因变异进行详尽的搜索。对于这项建议，我们将把大规模平行的人类外显子组和靶向测序数据与先前收集的AA结节病家系的基因和表型数据结合起来，以识别未发现的基因变异。我们广泛的、独一无二的样本将最大限度地提高检测RV关联性的能力，并帮助建立阶段，这对了解变异的分子生理学至关重要。我们将1)通过外显子组测序确定编码区变体，2)通过靶向重测序捕获先前研究确定的39个区域的编码和非编码区序列的变体，以及3)在独立的样本中复制真正的正CV和RV效应。我们组建的团队领导了AAS中结节病基因的搜索，我们拥有肺病学、遗传学、流行病学、基因组测序、生物统计学和生物信息学方面的专业知识，是世界上唯一完全准备成功完成拟议项目的团队。所产生的数据肯定会确定候选的因果变异，为功能研究提供基本的见解，并导致重要的炎症新假说，从而不仅对结节病而且对其他炎症性疾病产生新的治疗方法。

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.