Variation in the selenoprotein S gene locus is associated with coronary heart disease and ischemic stroke in two independent Finnish cohorts

Abstract

Selenoprotein S (SEPS1) is a novel candidate gene involved in the regulation of inflammatory response and protection from oxidative damage. This study explored the genetic variation in the SEPS1 locus for an association with CVD as well as with quantitative phenotypes related to obesity and inflammation. We used the case-cohort design and time-to-event analysis in two separate prospectively followed population-based cohorts FINRISK 92 and 97 (n = 999 and 1,223 individuals, respectively) to study the associations of five single nucleotide polymorphisms with the risk for coronary heart disease (CHD) and ischemic stroke events. We found a significant association with increased CHD risk in females carrying the minor allele of rs8025174 in the combined analysis of both cohorts [hazard ratio (HR) 2.95 (95% confidence interval: 1.37-6.39)]. Another variant, rs7178239, increased the risk for ischemic stroke significantly in females [HR: 3.35 (1.66-6.76)] and in joint analysis of both sexes and both cohorts [HR: 1.75 (1.17-2.64)]. These results indicate that variation in the SEPS1 locus may have an effect on CVD morbidity, especially in females. This observation should stimulate further investigations of the role of this gene and protein in the pathogenesis of CVD.

SEPS1 Gene is Activated during Astrocyte Ischemia and Shows Prominent Antiapoptotic Effects

“…Our data showing that SEPS1 exerts a protective role against astrocyte ischemia strengthen the observation reported by others that SEPS1 gene mutations that impair or limit protein function could account for an enhanced predisposition to ischemic damage after stroke (Alanne et al 2007). Conversely, no association between SEPS1 promoter polymorphism and cerebrovascular disease could be observed in a recent study (Hyrenbach et al 2007).…”

“…Consistent with this SEPS1 function, its overexpression has been shown to enhance the tolerance of pancreatic β cells to oxidative stress (Gao et al 2004) as well as the resistance of macrophages to ER-stress-induced apoptosis (Kim et al 2007). In addition, the recent report indicating that mutations in SEPS1 are associated with a higher predisposition to ischemic stroke in humans (Alanne et al 2007) suggests a key role for this protein in protection against brain ischemia. In this paper, we show that SEPS1 expression is upregulated in astrocytes in response to both in vitro ischemia and ER stress inducers.…”

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

“…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.…”

Selenoprotein S expression in reactive astrocytes following brain injury

“…Single nucleotide polymorphisms in SelS promoter impair SelS expression and prompt a basal pro-inflammatory state in humans that is characterized by increased release of inflammatory cytokines (Curran et al, 2005). Variations in SelS promoter sequence have also been associated to higher susceptibility to diseases linked to inflammation such as ischemic stroke, coronary heart disease, preeclampsia, and gastric cancer (Alanne et al, 2007;Moses et al, 2008;Shibata et al, 2009). SelS link to inflammation is confirmed by in vitro studies showing that SelS regulates the production of inflammatory cytokines (Curran et al, 2005;Gao et al, 2006).…”