Sarcoidosis is a granulomatous inflammatory disease often dubbed a ?medical mystery? yet significantly understudied. While it is known that sarcoidosis likely involves host genetic susceptibility and an innate and adaptive immune response to infectious, organic or inorganic agents, the mechanisms by which granulomas form and the determinants of severity and manifestation of disease remain elusive. Over the past several years, our team has led the charge to define the role of genetics in sarcoidosis. Specifically, under our current funding, we have published 13 papers with 3 more soon to be submitted describing genes for susceptibility, severity, ancestry specific and organ-specific effects. However, the mechanism(s) by which associated genetic variants influence sarcoidosis are still largely unknown. Our proposal will close this knowledge gap by characterizing functional variants and the tissue(s) in which they operate by 1) identifying differentially expressed (DE) genes in granulomatous tissue and blood, 2) characterizing the expression of DE and previously associated genes by specific cell type, 3) identifying tissue or cell-specific eQTLs for DE and previously associated genes, 4) creating clinical profiles of patients carrying risk alleles and 5) replicating our findings in an independent cohort. Specifically, in Aim 1, we will identify novel candidate genes and their most likely causal variants to be investigated in our future mechanistic studies of sarcoidosis susceptibility and persistence via DE analysis of RNA sequencing data of whole blood from both EA and AA sarcoidosis patients and matched controls AND DE analysis of granulomatous tissue from a subset of these same patients compared to healthy tissue. Additionally, we will perform eQTL analysis using the transcriptomic data from blood and tissue described above and ancestry-informative genome-wide genotyping data.
In Aim 2, we will define the cell subsets in which the most likely causal variants operate and identify novel cell-specific effects by DE analysis of RNA sequencing data from blood-derived single cells in our cohort of EA and AA cases and matched controls. In order to identify cell-type specific eQTLs, analysis of the genotype and single cell transcriptomic data will also be performed. Finally, in Aim 3 we will replicate our list of candidate genes, their most likely causal variants and the specific cell type in which they influence disease using blood, tissue and single cells from a cohort of patients recruited based on the demographic and clinical criteria that are associated with our causal variants. Our work will be greatly facilitated by the extensive genotype, clinical and environmental data on our existing cohort AND the recently established Sarcoidosis Research Unit from both of which we have strong preliminary data to support the studies proposed herein. In summary, when this grant is complete, we will know the likely causal variants, the tissue and cell-types in which they function and the clinical characteristics of the patients in which they are most likely to be enriched from which detailed mechanistic experiments can be designed.

Public Health Relevance

Sarcoidosis is a debilitating disease that affects both African and European Americans, women and men. It involves a dysregulation of the immune system and includes both environmental and genetic risk factors. Identifying likely causal variants and characterizing the tissues and cells in which they are active will bridge a significant gap in our understanding of sarcoidosis and allow us to mechanistically investigate its etiology and pathology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL113326-06A1
Application #
9662259
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gan, Weiniu
Project Start
2012-04-01
Project End
2023-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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Moller, David R; Rybicki, Ben A; Hamzeh, Nabeel Y et al. (2017) Genetic, Immunologic, and Environmental Basis of Sarcoidosis. Ann Am Thorac Soc 14:S429-S436
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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
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

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