Gene-environment interactions in sarcoidosis: challenge and opportunity

Abstract

Susceptibility to most human diseases is polygenic, with complex interactions between functional polymorphisms of single genes governing disease incidence, phenotype, or both. In this context, the contribution of any discrete gene is generally modest for a single individual, but may confer substantial attributable risk on a population level. Environmental exposure can modify the effects of a polymorphism, either by providing a necessary substrate for development of human disease or because the effects of a given exposure modulate the effects of the gene. In several diseases, genetic polymorphisms have been shown to be context-dependent, i.e. the effects of a genetic variant are realized only in the setting of a relevant exposure. Since sarcoidosis susceptibility is dependent on both genetic and environmental modifiers, the study of gene-environment interactions may yield important pathogenetic information and will likely be crucial for uncovering the range of genetic susceptibility loci. However, the complexity of these relationships implies that investigations of geneenvironment interactions will require the study of large cohorts with carefully-defined exposures and similar clinical phenotypes. A general principle is that the study of gene-environment interactions requires a sample size at least several-fold greater than for either factor alone. To date, the presence of environmental modifiers has been demonstrated for one sarcoidosis susceptibility locus, HLA-DQB1, in African-American families. This article reviews general considerations obtaining for the study of gene-environment interactions in sarcoidosis. It also describes the limited current understanding of the role of environmental influences on sarcoidosis susceptibility genes.

Sarcoidosis and its otolaryngological implications

“…Genetic factors can be important in deWning the pattern of disease presentation, its severity and prognosis. Several investigators have searched for associations with human leucocyte antigen (HLA)-related genes that may confer susceptibility to sarcoidosis, suggesting that haplotype HLA-DRB1*1101 can predispose people to development of this disease [18][19][20].…”

Cat litter is a possible trigger for sarcoidosis

“…Silica granulomatosis is a delayed hypersensitivity response to crystalline silica. The biological plausibility of a relationship between exposure to silica and autoimmune and inflammatory disorders has already been proposed [1][2][3]. Recently, SOLÀ et al [6] reported a very interesting case suggesting a new association between ingestion of anhydrous colloidal silica (a vehicle for some oral drug formulations) and sarcoidosis.…”

“…Many causative agents are considered to be involved in the pathogenesis [1][2][3][4][5]. Geneenvironment interactions offer the potential for strengthening the evidence of causation between exposures and sarcoidosis.…”

“…Sarcoidosis susceptibility depends on both environmental and genetic modifiers [1,4,5]. Inflammation in sarcoidosis is characterised by ongoing T-cell and macrophage activity and granuloma formation reflected by an increase of serological markers of inflammation or abnormality in glucose metabolism demonstrated as high uptake on 18 F-FDG PET/CT [4,9].…”

An American Thoracic Society Official Research Statement: Future Directions in Lung Fibrosis Research

“…To that end, models that are capable of investigating multiple biologic processes simultaneously are more likely to provide insights into human disease pathogenesis. Such a "multiple hit" hypothesis has been forwarded for many ILDs, such as hypersensitivity pneumonitis (12), sarcoidosis (13), and IPF (14). Determining whether this hypothesis is true will require models that take multiple genetic, environmental, and host immunological aberrations into account.…”