Genetic variation in selenoprotein S influences inflammatory response

Abstract

Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1beta and TNF-alpha. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory cytokines. One promoter variant, -105G --> A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-alpha. To investigate further the significance of the observed associations, we genotyped -105G --> A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant association with both TNF-alpha (P = 0.0049) and IL-1beta (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.

Gene–gene interaction among cytokine polymorphisms influence susceptibility to aggressive periodontitis

“…Variations in the SEPS1 gene are associated with the circulating levels of inflammatory cytokines IL-1b, IL-6 and TNF-a. 34 A recent study conducted in two independent Finnish cohorts indicated that variation in the SEPS1 locus may have an effect on cardiovascular disease morbidity, especially in females. 35 Our results seem to suggest the involvement of SEPS1 as host factor that might be also involved in determining the individual susceptibility to AgP.…”

Selenium biochemistry and its role for human health

“…200 A particular polymorphism of SelS was proven to be responsible for increased plasma level of the inflammatory cytokines. 201 A possible increased risk of several inflammatory diseases could be the consequence, but a direct correlation with stroke, autoimmune disorders or inflammatory bowel disease is still not proven. 188 As a whole, Se participates in the immune response through several actions: it regulates the balance of activity in the eicosanoid synthesis pathways, leading to preferential synthesis of leukotrienes and prostacyclins over thromboxanes and prostaglandins, and down-regulates cytokine and adhesion molecule expression.…”

Transcriptomics and functional genetic polymorphisms as biomarkers of micronutrient function: focus on selenium as an exemplar

“…Reporter gene experiments indicate that the SNP have functional consequences. Second, SelS is another selenoprotein recently found to have a function in the ER stress response (33)(34)(35) . An SNP in the SELS promoter at position -105 is regarded as being functionally significant as it modulates levels of inflammatory markers such as TNF-a and interleukin (33) .…”

“…Second, SelS is another selenoprotein recently found to have a function in the ER stress response (33)(34)(35) . An SNP in the SELS promoter at position -105 is regarded as being functionally significant as it modulates levels of inflammatory markers such as TNF-a and interleukin (33) . Third, SNP have been identified in the promoter region of the GPX3 gene coding for the plasma glutathione peroxidase GPx3 and gene reporter experiments suggest that these affect promoter activity (36,37) .…”