The role of the selenoprotein S (SELS) gene −105G>A promoter polymorphism in inflammatory bowel disease and regulation of SELS gene expression in intestinal inflammation

Abstract

Recently, a -105G>A promoter polymorphism coding for selenoprotein S (SELS) has been shown to increase proinflammatory cytokine expression. We, therefore, analyzed SELS expression and potential phenotypic consequences of the -105G>A polymorphism in patients with inflammatory bowel disease (IBD). SELS mRNA was measured by quantitative polymerase chain reaction (PCR) in intestinal epithelial cells (IEC) after stimulation with proinflammatory cytokines and in human colonic biopsies of IBD patients as well as in murine models of ileitis and murine cytomegalovirus (MCMV) colitis. Genomic DNA from 563 individuals (Crohn's disease: n = 205; ulcerative colitis: n = 154; controls: n = 204) was analyzed for the presence of the SELS-105G>A polymorphism and the three nucleotide-binding oligomerization domain-containing protein 2 (NOD2)/caspase recruitment domain-containing protein 15 (CARD15) variants p.Arg702Trp, p.Gly908Arg and p.Leu1007fsX1008. SELS mRNA expression was increased in IEC after stimulation with proinflammatory cytokines, while its expression was not significantly altered in murine ileitis and MCMV colitis and in inflamed ileal and colonic lesions in IBD patients compared with normal controls. The SELS-105G>A polymorphism was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype or serum tumor necrosis factor alpha (TNF-alpha) levels in these patients. Medium serum TNF-alpha was 1.27 pg/ml in IBD patients, while none of the controls had TNF-alpha concentrations above the detection threshold (P < 0.0001). SELS mRNA expression is upregulated by proinflammatory cytokines in IECs but the SELS-105G>A polymorphism is not associated with IBD susceptibility and does not contribute to a certain disease phenotype or increased TNF-alpha levels in IBD patients.

Evidence for STAT4 as a Common Autoimmune Gene: rs7574865 Is Associated with Colonic Crohn's Disease and Early Disease Onset

“…In line with previous reports of significant associations of genetic variants in the STAT4 gene with the risk for autoimmune diseases such as SLE, rheumatoid arthritis [23], [27], [32] and psoriasis, [23], [36] our study could identify the STAT4 SNP rs7574865 also to be associated with the susceptibility to CD. However, this association to CD did not reach the extent of significance or clinical relevance shown for other CD susceptibility genes such as NOD2 / CARD15 and IL23R [5], [13], [14], [41]–[43]. For all other STAT4 gene variants investigated (rs11889341, rs7568275, rs8179673, rs10181656, rs7582694 and rs10174238), our analysis did not reveal any significant association with CD or UC susceptibility.…”

Expression of the selenoprotein S (SELS) gene in subcutaneous adipose tissue and SELS genotype are associated with metabolic risk factors

“…Previous studies have suggested that the SELS gene is dysregulated in diabetes, and the data presented here indicate that the C3705T and/or the A5227G polymorphisms may play a role in this context. However, the C-105T polymorphism, which showed the strongest association with circulating proinflammatory cytokines [10] but no direct association with inflammatory bowel disease [9] or rheumatoid arthritis [14], was not associated with metabolic risk factors analyzed in this study.…”

Polymorphisms in the selenoprotein S and 15-kDa selenoprotein genes are associated with altered susceptibility to colorectal cancer

“…The observed difference in allele frequency of rs34713741 between patients with rectal cancer and controls (Tables 3, 4, 5) may reflect the close proximity (*100 bp) and likely linkage of rs28665122 and rs3471374 and changes in inflammatory events in the rectum, especially since altered inflammatory processes have been associated with increased CRC risk [17]. The previous failure to find any association between genotype for rs28665122 and susceptibility to inflammatory bowel disease [27] may reflect the small size of the population examined in that study. The present results suggest investigation of SELS association with gut inflammation using either mechanistic approaches or larger population groups would be worthwhile.…”