The non-caseating granuloma is an important pathologic consequence in many rare diseases, including those of unknown cause, such as sarcoidosis, and of known cause, such as chronic beryllium disease (CBD). Additionally, these disorders share similar clinical presentation and pathophysiologic mechanisms involving both innate and adaptive immunity. Specifically, both disorders likely require interaction of Human Leukocyte Antigen (HLA) Class II dependent antigen presenting cells with oligoclonal CD4+ T lymphocytes. Consequently, an aberrant production of cytokines and growth factors that promote granulomatous inflammation ensues. Genetic susceptibility is an important determinant in both of these multigenic diseases. To date, most studies of these disorders have examined the diseases individually, usually targeting single or small groups of candidate genes, often yielding ambiguous or negative results. The central goal of this R21 application is to use whole genome single nucleotide polymorphism (SNP) DNA scans to identify genetic regions that confer granulomatous disease risk. We hypothesize that there are shared polymorphic sites within the human genome that confer risk for granulomatous disease. Beyond the scope of this study, our central hypothesis is that the shared genetic regions reflect shared genetic susceptibility factors between these diseases. In this proposal we will first determine genetic regions or SNPs associated with CBD compared to beryllium-exposed non-diseased controls using genome scans. In turn, we will use this same approach to define genetic regions associated with sarcoidosis, using the NIH A Case Control Etiologic Study of Sarcoidosis (ACCESS) cases and matched controls. The DNA arrays we will use contain 116,204 SNPs spaced at a median physical distances of approximately 8.5 kb across the genome. We will control for population stratification in both the CBD and sarcoidosis populations using genome control methods. Data will be compared both between diseased and non-affected groups and between the two granulomatous disease groups, in order to define shared genetic regions of putative relevance to disease pathogenesis. We will then confirm the association of these regions with both diseases in a case control study involving two larger populations of CBD and ACCESS cases and controls. With results from genome scans confirmed in a second population as preliminary data, it becomes feasible to propose future studies that would involve detailed fine mapping and sequencing of shared genes of importance to the family of rare granulomatous disorders, and that evaluate the underlying immunopathogenic mechanisms associated with these shared genetic factors. ? ? ?
| Samuel, George; Maier, Lisa A (2008) Immunology of chronic beryllium disease. Curr Opin Allergy Clin Immunol 8:126-34 |
