The role of environmental exposures and gene-environment interactions in the etiology of systemic lupus erythematous

Abstract

Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease, whose etiology includes both genetic and environmental factors. Individual genetic risk factors likely only account for about one-third of observed heritability among individuals with a family history of SLE. A large portion of the remaining risk may be attributable to environmental exposures and gene-environment interactions. This review focuses on SLE risk associated with environmental factors, ranging from chemical and physical environmental exposures to lifestyle behaviors, with the weight of evidence supporting positive associations between SLE and occupational exposure to crystalline silica, current smoking, and exogenous estrogens (e.g., oral contraceptives and postmenopausal hormones). Other risk factors may include lifestyle behaviors (e.g., dietary intake and sleep) and other exposures (e.g., ultraviolet [UV] radiation, air pollution, solvents, pesticides, vaccines and medications, and infections). Alcohol use may be associated with decreased SLE risk. We also describe the more limited body of knowledge on gene-environment interactions and SLE risk, including IL-10, ESR1, IL-33, ITGAM, and NAT2 and observed interactions with smoking, UV exposure, and alcohol. Understanding genetic and environmental risk factors for SLE, and how they may interact, can help to elucidate SLE pathogenesis and its clinical heterogeneity. Ultimately, this knowledge may facilitate the development of preventive interventions that address modifiable risk factors in susceptible individuals and vulnerable populations.

Keywords: SLE; environment; gene-environment interactions; genetics; risk factors; systemic lupus erythematosus.

Figure 1.

Common symptoms and manifestations of systemic lupus erythematosus based on the 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria.

Figure 2.

Proposed mechanisms involving genetic and environmental risk factors and gene-environment interactions and estimated attributable contribution to the etiology and onset of systemic lupus erythematosus (SLE). While a proportion of genetic risk factors (yellow) and environmental exposures (blue) have been shown to be independently associated with SLE risk, it is hypothesized that the majority risk can attributed to gene-environment interactions (green).

Figure 3

Reported gene-environment interactions and SLE risk by environmental exposure and study population.