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.

Public Health Relevance

Sarcoidosis is a debilitating disease that affects African Americans (AAs) far more frequently and severely than US whites. Identifying common and rare causal variants and characterizing their role in AA sarcoidosis susceptibility will bridge a significant gap in our understanding of sarcoidosis genetics and provide insight into etiology and pathology.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL113326-03
Application #
8645728
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Gan, Weiniu
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Rivera, Natalia V; Ronninger, Marcus; Shchetynsky, Klementy et al. (2016) High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences. Am J Respir Crit Care Med 193:1008-22
Lareau, Caleb A; Adrianto, Indra; Levin, Albert M et al. (2015) Fine mapping of chromosome 15q25 implicates ZNF592 in neurosarcoidosis patients. Ann Clin Transl Neurol 2:972-7
Lareau, Caleb A; White, Bill C; Montgomery, Courtney G et al. (2015) dcVar: a method for identifying common variants that modulate differential correlation structures in gene expression data. Front Genet 6:312
Bello, Ghalib A; Adrianto, Indra; Dumancas, Gerard G et al. (2015) Role of NOD2 Pathway Genes in Sarcoidosis Cases with Clinical Characteristics of Blau Syndrome. Am J Respir Crit Care Med 192:1133-5
Fischer, Annegret; Ellinghaus, David; Nutsua, Marcel et al. (2015) Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk. Am J Respir Crit Care Med 192:727-36
Levin, Albert M; Adrianto, Indra; Datta, Indrani et al. (2015) Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans. Am J Respir Cell Mol Biol 53:206-16
Fischer, Annegret; Rybicki, Benjamin A (2015) Granuloma genes in sarcoidosis: what is new? Curr Opin Pulm Med 21:510-6
Levin, Albert M; Adrianto, Indra; Datta, Indrani et al. (2014) Performance of HLA allele prediction methods in African Americans for class II genes HLA-DRB1, -DQB1, and -DPB1. BMC Genet 15:72
Li, Jia; Yang, James; Levin, Albert M et al. (2014) Efficient generalized least squares method for mixed population and family-based samples in genome-wide association studies. Genet Epidemiol 38:430-8
Levin, Albert M; Iannuzzi, Michael C; Montgomery, Courtney G et al. (2014) Admixture fine-mapping in African Americans implicates XAF1 as a possible sarcoidosis risk gene. PLoS One 9:e92646

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