Sarcoidosis is a multi-organ granulomatous, inflammatory disease of uncertain etiology, with 90% of cases presenting pulmonary involvement. Despite convincing evidence that sarcoidosis likely arises when a genetically-susceptible host is exposed to a causative environmental agent, studies of environmental agents and disease risk suggest that there is more than one single environmental trigger. Further, there have been few gene-environment interaction (GxE) studies of disease etiology published to date; those few have focused on the class II genes within the Human Leukocyte Antigen (HLA) region, the most studied and validated region associated with sarcoidosis risk. In the United States, African Americans are at highest risk for sarcoidosis; the adjusted annual incidence among African Americans is roughly three times that of European Americans (35.5/100,000 versus 10.9/100,000). Among African Americans, the disease is also more likely to be chronic and severe. We recently performed the first gene-environment-wide interaction study (GEWIS) of insecticide exposure and sarcoidosis risk in the Ancestry Mapping of Sarcoidosis Study (AMASS), a large study of sarcoidosis in African Americans. Using our recently-developed methodology, we identified a genome-wide significant GxE association in the FUT9 gene. To build on this effort, the current proposal will focus on the family-based portion of AMASS (503 families, including 818 sarcoidosis cases and 632 healthy family members), which has a rich resource of both environmental exposure and genetic (genome-wide genotyping, targeted/full exome sequencing, and imputed HLA Class I and II genes) data available. First, we propose to identify environmental exposures associated with sarcoidosis risk (Aim 1). Where existing sarcoidosis studies have been limited to investigating environmental exposures in isolation, we will move beyond this trend by using latent-class analysis (LCA) to identify patterns across multiple environmental exposures. Associated environmental exposures (individual and/or LCA-identified multi-exposure groups) will be evaluated for GxE effects (Aim 2). Current family-based GEWIS have focused on the exhaustive strategy of testing all genetic variants. To attempt to improve power, we will extend a two-step strategy to our study of related and admixed individuals and compare both exhaustive and two-step GEWIS strategies via simulation. The strategy with the highest power that also controls the type-1 error rate will be selected for GxE testing for the environmental factors from Aim 1. In summary, we propose multiple innovations to the fields of both GxE analysis and sarcoidosis research that increase the chance for better understanding of the etiology of this debilitating disease.
Sarcoidosis is a multi-organ granulomatous, inflammatory disease of uncertain etiology, with the lung being the most commonly affected organ (i.e. 90% of cases presenting with pulmonary involvement). While the scientific literature supports both genetic and environmental components to disease risk, evaluation of gene-environment interactions in sarcoidosis have been restricted to the human leukocyte antigen class II genes, and there is only one gene- environment-wide association study (GEWIS) published in the literature to date. Using a GEWIS approach, we will utilize rich sets of both genetic and environmental data gathered for an existing African American family-based study of sarcoidosis to identify gene-environment interactions associated with disease pathogenesis in this minority population in the United States that suffers disproportionately from this disease.
