Abstract
The influence and effect of cigarette smoking in sarcoidosis is unclear. Here, we evaluated gene-environment interaction between multiple genetic variants including HLA genes and smoking in sarcoidosis defined by two clinical phenotypes, Löfgren’s syndrome (LS) and patients without Löfgren’s syndrome (non-LS). To quantify smoking effects in sarcoidosis, we performed a gene-environment interaction study in a Swedish population-based case-control study consisting of 3,713 individuals. Cases and controls were classified according to their cigarette smoking status and genotypes by Immunochip platform. Gene-smoking interactions were quantified by an additive interaction model using a logistic regression adjusted by sex, age and first two principal components. The estimated attributable proportion (AP) was used to quantify the interaction effect. Assessment of smoking effects with inclusion of genetic information revealed 53 (in LS) and 34 (in non-LS) SNP-smoking additive interactions at false discovery rate (FDR) below 5%. The lead signals interacting with smoking were rs12132140 (AP = 0.56, 95% CI = 0.22–0.90), p = 1.28e-03) in FCRL1 for LS and rs61780312 (AP = 0.62, 95% CI = 0.28–0.90), p = 3e-04) in IL23R for non-LS. We further identified 16 genomic loci (in LS) and 13 (in non-LS) that interact with cigarette smoking. These findings suggest that sarcoidosis risk is modulated by smoking due to genetic susceptibility. Therefore, patients having certain gene variants, are at a higher risk for the disease. Consideration of individual’s genetic predisposition is crucial to quantify effects of smoking in sarcoidosis.
Highlights
Sarcoidosis is a multi-systematic inflammatory disorder with an unknown etiology
Löfgren’s syndrome (LS) patients who had both risk factors, i.e., smoking and risk allele had a double exposure risk (OR = 2.92, 95% confidence intervals (CI): 1.68–5.07) with an attributable proportion of 56% disease risk compared to LS patients who had one risk factor, i.e., smoking and no risk allele (OR = 1.18 95% CI: 0.64–2.21) or risk allele and no smoking (OR = 1.09 95% CI: 0.82–1.46)
Non-LS patients who had both factors, i.e., risk allele and smoking had double exposure risk (OR = 3.23, 95% CI: 1.75–5.97) with an attributable proportion of 62% disease risk compared to non-LS patients with one risk factor, i.e., smoking and no risk allele (OR = 1.18, 95% CI 0.6–2.31) or risk allele and no smoking (OR = 1.05, 95% CI: 0.84–1.31)
Summary
Sarcoidosis is a multi-systematic inflammatory disorder with an unknown etiology. The disease can affect any organ in the body; the lungs and lymphatic system are the most common targets. A recent study by our group showed that the genetic architecture of sarcoidosis phenotypes, LS and non-LS, differed in their genetic susceptibility and activity of cells, suggesting distinct genetic architectures and molecular mechanisms between these phenotypes[8]. Epidemiological studies have reported that environmental factors play a role in the disease development. Smoking is one of the environmental factors believed to be associated with the disease; evidence from epidemiological studies showed conflicting findings. On regards to smoking effects and indices of disease, Schildge[19] showed that smokers with sarcoidosis had a lower albumin concentration in broncoalveolar lavage fluid (BALF) compared to non-smokers[19]. In all the aforementioned studies, genetic information of smokers and non-smokers was not considered in their assessment
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