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.

Life factors acting on systemic lupus erythematosus

“…Previously, epidemiological studies showed that there was no significant association between alcohol consumption and SLE ( 110 , 162 – 166 ). However, in the last several decades, several studies have consistently suggested that moderate alcohol consumption was negatively associated with the risk of SLE, irrespective of the type of alcoholic beverage ( 3 , 112 , 115 , 167 , 168 ). A meta-analysis of six case-control studies and one cohort study published in 2008 revealed that moderate alcohol consumption likely has a protective effect against the development of SLE ( 169 ).…”

“…Recent research focused on cigarette smoking affecting clinical manifestations of patients with SLE has indicated that cigarette smoking was associated with photosensitivity, cutaneous damage, active SLE rash ( 124 – 127 ), higher SLE Disease Activity Index (SLEDAI) score ( 128 ), pleuritis, peritonitis, metabolic syndrome ( 129 ), neuropsychiatric symptoms ( 130 , 131 ), vascular necrosis ( 132 ), thrombotic events ( 133 – 136 ), cardiovascular disease ( 137 ), peripheral vascular disease ( 138 , 139 ), and production of anti-phospholipid antibodies ( 136 ). Moreover, smoking lowers the efficacy of medicines used to treat SLE ( 3 , 140 , 141 ). Likewise, a prospective cross-sectional study of Chinese SLE patients performed in 2015 reported that cigarette smoking causes the development and worsening of symptoms in SLE patients, including photosensitivity, nephropathy, proteinuria, compared with those in nonsmokers (after adjustment for age and gender), whereas SLEDAI scores were not significantly different in smokers and non-smokers ( 142 ).…”

“…If UVR is a trigger for SLE onset, glutathione S-transferases (GSTs, detoxification enzymes that protect cells from attack by reactive electrophiles that are produced by certain stressors, such as infection) may play a key role ( 3 ). The isoenzyme Mu of GST (GSTM1) is dominantly inherited.…”

“…The prevalence rate of SLE worldwide is about 20–70 per 100,000 general population ( 1 , 2 ). The exact etiology of SLE remains unclear, but genetic risk loci, such as N-acetyltransferase 2 (NAT2) slow acetylator genotype, and environmental factors are crucial in the development of susceptibility to SLE ( 3 , 4 ). Although many SLE susceptibility genes have been identified recently, gene therapy approaches remain a distant prospect from the point of view of the clinical treatment ( 5 ).…”

Understanding the Concept of Pre-Clinical Autoimmunity: Prediction and Prevention of Systemic Lupus Erythematosus: Identifying Risk Factors and Developing Strategies Against Disease Development

“…This likely leads to an acceleration of underlying and brewing autoimmunity, allowing it to manifest in SLE. These factors include current cigarette smoking, obesity (in particular, at younger ages), childhood and adult trauma, stress, posttraumatic stress disorder, low or no alcohol intake, environmental air pollution, environmental silica, and hormonal exposures and reproductive factors among women [reviewed in (58,119)]. While is it not known whether these environmental risk factors work via similar or disparate biologic pathways, nor whether they are perhaps also inextricably linked to other societal risk factors that are more difficult to measure, the picture of how and the extent to which they contribute to SLE susceptibility is coming into focus.…”