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, ie, the effects of a genetic variant are realized only in the setting of a relevant exposure. Because 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. The complexity of these relationships implies, however, that investigations of gene-environment 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 severalfold 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.

Figure 1

Proposed model for development of sarcoidosis. Individuals inherit a spectrum of genetic polymorphisms that may influence susceptibility to disease, but that are only realized in the context of a relevant exposure. Disease-associated susceptibility genes may influence position on this matrix differentially, depending on the function of the individual gene product, and on the influence of gene-gene interactions. The relevance of environmental exposures may be influenced by their duration, intensity, timing or context. A similar model might also describe disease phenotype.

Figure 2

Theoretical gene-environment relationships. Panels A and B depict diseases influenced only by the gene or environmental variable, while Panel C demonstrates an additive relationship for a dominant mutation “a” with environmental exposure modeled as a continuous variable. Panel D, a true (biologic) gene-environment interaction, where the effect of the genotype is variably influenced by the exposure. Modified from [18].

Figure 2

Theoretical gene-environment relationships. Panels A and B depict diseases influenced only by the gene or environmental variable, while Panel C demonstrates an additive relationship for a dominant mutation “a” with environmental exposure modeled as a continuous variable. Panel D, a true (biologic) gene-environment interaction, where the effect of the genotype is variably influenced by the exposure. Modified from [18].

Figure 3

Possible gene-environment relationships. Exposure “A” and Genotype “X” represent a gene or environmental exposure requisite for development of the disease. Modifier genes (T) or exposures (G) also influence susceptibility or phenotypic determination.

Figure 4

Influence of random misclassification error on relative risk estimates. The estimated relative risk for the outcome depends on the degree actual risk (RR true) and the accuracy of assessing the exposure of interest [24]. For a hypothetical observer correctly classifying exposure 80% of the time, a true relative risk of 2.5 would be estimated to be 2.0.

Figure 5

Concept of Mendelian randomization. The relationship of the exposure to development of disease can be estimated by measuring the association of genotype with disease and on development of an internal phenotype (IP) that is directly related to the disease, thereby allowing an estimate of the relation between IP and the disease. If the gene can mediate other internal phenotypes, then no causality can be assigned to the exposure. Modified from [30].