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Genetic variation in selenoprotein S influences inflammatory response

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journal contribution
posted on 2005-11-01, 00:00 authored by J Curran, Jeremy Jowett, K Elliott, Yuan Gao, K Gluschenko, W Jianmin, D Azim, G Cai, M Mahaney, A Comuzzie, T Dyer, Ken WalderKen Walder, P Zimmet, J MacCluer, Gregory Collier, A Kissebah, J Blangero
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-1b and TNF-a. 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-a. 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-a (P = 0.0049) and IL-1b (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.

History

Journal

Nature genetics

Volume

37

Pagination

1234 - 1241

Location

New York, N.Y.

Open access

  • Yes

ISSN

0028-0836

eISSN

1476-4687

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal; C Journal article

Copyright notice

2005, Nature Publishing Group

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