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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-1β and TNF-α. 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-α. 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-α (P = 0.0049) and IL-1β (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.

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Figure 1
Figure 2: Pattern of linkage disequilibrium in SEPS1.
Figure 3: Results of robust measured genotype analysis for marginal associations between SEPS1 SNPs and plasma cytokine measures.
Figure 4: Effect of SEPS1 SNP −105G → A on expression of SEPS1 after challenging HepG2 cells with tunicamycin.
Figure 5: siRNA suppression of SEPS1 in macrophages.

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Acknowledgements

This work was supported by grants from the National Institutes of Health. Take Off Pounds Sensibly, Inc. provided funds for establishment of the family database and clinical phenotyping. This work was also supported by grants from the National Center for Research Resources to the General Clinical Research Centers at the Medical College of Wisconsin and the University of Texas Health Science Center San Antonio. The statistical genetics computer package, SOLAR, is supported by a grant from the National Institutes of Mental Health. The supercomputing facilities used for this work at the SBC Genetics Computing Center were supported in part by a gift from the SBC Foundation. Funds for resequencing, genotyping and functional and statistical analyses were provided by ChemGenex Pharmaceuticals Ltd., Australia.

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Correspondence to John Blangero.

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Competing interests

Funds for resequencing, genotyping and functional and statistical analyses were provided by ChemGenex Pharmaceuticals, which has a patent on SELS in relation to its role in multiple diseases. G.R.C. and P.Z. have personal financial interests in ChemGenex. G.R.C. is also the Chief Executive Officer and Managing Director of ChemGenex. P.Z. and J.B. are members of the Scientific Advisory Board of ChemGenex. J.B. also serves as Senior Director of Human Genomics, and K.R.W. serves as Senior Director of Research and Development.

Supplementary information

Supplementary Table 1

Selenoprotein S genetic variation identified in the sample. (PDF 26 kb)

Supplementary Table 2

Distribution of relative pairs in the population sample of 522 individuals from 92 families. (PDF 15 kb)

Supplementary Table 3

siRNA primer sequences. (PDF 13 kb)

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Curran, J., Jowett, J., Elliott, K. et al. Genetic variation in selenoprotein S influences inflammatory response. Nat Genet 37, 1234–1241 (2005). https://doi.org/10.1038/ng1655

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