Human Genetics

, Volume 122, Issue 3–4, pp 355–365 | Cite as

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

  • Mervi AlanneEmail author
  • Kati Kristiansson
  • Kirsi Auro
  • Kaisa Silander
  • Kari Kuulasmaa
  • Leena Peltonen
  • Veikko Salomaa
  • Markus Perola
Original Investigation


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.


Ischemic Stroke Endoplasmic Reticulum Stress Minor Allele SEPS1 Gene SEPS1 Locus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank all participants of the FINRISK 92 and 97 studies. KTL Analytical Biochemistry laboratory is acknowledged for the laboratory measurements. Mrs. Anne Nyberg, Mrs. Siv Knaapila and Mrs. Minna Suvela are thanked for their skillful contribution in the genotyping process. Mrs. Siv Knaapila and MSc. Minttu Jussila are thanked for their participation in the DNA aliquotting process. MORGAM Data Centre is thanked for data management and assistance in the analysis procedures. We greatly appreciate the help from Dr. Joanne Curran during TagMan genotyping and at planning stage of the project. This study was supported by the Research Foundation of Orion Corporation, the Finnish Foundation for Cardiovascular Research, Aarne Koskelo Foundation, Jenny and Antti Wihuri Foundation and Sigrid Juselius Foundation. This study is a part of the GenomEUtwin—project (, which is supported by the European Commission under the programme “Quality of Life and Management of the Living Resources” of fifth Framework Programme (no. QLG2-CT-2002-01254).

Supplementary material

439_2007_402_MOESM1_ESM.doc (52 kb)
Supplementary table 1. Minor allele associated risk for incident coronary heart disease and ischemic stroke event of SNPs rs28665122, rs4965373 and rs9874 (DOC 52 kb)
439_2007_402_MOESM2_ESM.doc (43 kb)
Supplementary table 2. Haplotype carriership associated risk of incident coronary heart disease and ischemic stroke event (DOC 43 kb)


  1. Akishima Y, Akasaka Y, Ishikawa Y, Lijun Z, Kiguchi H, Ito K, Itabe H, Ishii T (2004) Role of macrophage and smooth muscle cell apoptosis in association with oxidized low-density lipoprotein in the atherosclerotic development. Mod Pathol 18:365–373CrossRefGoogle Scholar
  2. Auro K, Komulainen K, Alanne M, Silander K, Peltonen L, Perola M, Salomaa V (2006) Thrombomodulin gene polymorphisms and haplotypes and the risk of cardiovascular events: a prospective follow-up study. Arterioscler Thromb Vasc Biol 26:942–947PubMedCrossRefGoogle Scholar
  3. Barlow WE (1994) Robust variance estimation for the case-cohort design. Biometrics 50:1064–1072PubMedCrossRefGoogle Scholar
  4. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRefGoogle Scholar
  5. Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87:840–844PubMedGoogle Scholar
  6. Choy JC, Granville DJ, Hunt DW, McManus BM (2001) Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis. J Mol Cell Cardiol 33:1673–1690PubMedCrossRefGoogle Scholar
  7. Curran JE, Jowett JB, Elliott KS, Gao Y, Gluschenko K, Wang J, Abel Azim DM, Cai G, Mahaney MC, Comuzzie AG, Dyer TD, Walder KR, Zimmet P, MacCluer JW, Collier GR, Kissebah AH, Blangero J (2005) Genetic variation in selenoprotein S influences inflammatory response. Nat Genet 37:1234–1241PubMedCrossRefGoogle Scholar
  8. Evans A, Salomaa V, Kulathinal S, Asplund K, Cambien F, Ferrario M, Perola M, Peltonen L, Shields D, Tunstall-Pedoe H, Kuulasmaa K (2005) MORGAM (an international pooling of cardiovascular cohorts). Int J Epidemiol 34:21–27PubMedCrossRefGoogle Scholar
  9. Gao Y, Walder K, Sunderland T, Kantham L, Feng HC, Quick M, Bishara N, de Silva A, Augert G, Tenne-Brown J, Collier GR (2003) Elevation in Tanis expression alters glucose metabolism and insulin sensitivity in H4IIE cells. Diabetes 52:929–934PubMedCrossRefGoogle Scholar
  10. Gao Y, Feng HC, Walder K, Bolton K, Sunderland T, Bishara N, Quick M, Kantham L, Collier GR (2004) Regulation of the selenoprotein SelS by glucose deprivation and endoplasmic reticulum stress—SelS is a novel glucose-regulated protein. FEBS Lett 563:185–190PubMedCrossRefGoogle Scholar
  11. Gao Y, Hannan NRF, Wanyonyi S, Konstantopolous N, Pagnon J, Feng HC, Jowett JBM, Kim K-H, Walder K, Collier GR (2006) Activation of the selenoprotein SEPS1 gene expression by pro-inflammatory cytokines in HepG2 cells. Cytokine 33:246–251PubMedCrossRefGoogle Scholar
  12. Gao Y, Pagnon J, Feng HC, Konstantopolous N, Jowett JB, Walder K, Collier GR (2007) Secretion of the glucose-regulated selenoprotein SEPS1 from hepatoma cells. Biochem Biophys Res Commun 356:636–641PubMedCrossRefGoogle Scholar
  13. Gargalovic PS, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Baruch-Oren T, Berliner JA, Kirchgessner TG, Lusis AJ (2006) The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol 26:2490–2496PubMedCrossRefGoogle Scholar
  14. Gross M, Oertel M, Kohrle J (1995) Differential selenium-dependent expression of type I 5′-deiodinase and glutathione peroxidase in the porcine epithelial kidney cell line LLC-PK1. Biochem J 306( Pt 3):851–856PubMedGoogle Scholar
  15. Kim S, De Gruttola V (1999) Strategies for cohort sampling under the Cox proportional hazards model, application to an AIDS clinical trial. Lifetime Data Anal 5:149–172PubMedCrossRefGoogle Scholar
  16. Kim KH, Gao Y, Walder K, Collier GR, Skelton J, Kissebah AH (2007) SEPS1 protects RAW264.7 cells from pharmacological ER stress agent-induced apoptosis. Biochem Biophys Res Commun 354:127–132PubMedCrossRefGoogle Scholar
  17. Komulainen K, Alanne M, Auro K, Kilpikari R, Pajukanta P, Saarela J, Ellonen P, Salminen K, Kulathinal S, Kuulasmaa K, Silander K, Salomaa V, Perola M, Peltonen L (2006) Risk alleles of USF1 gene predict cardiovascular disease of women in two prospective studies. PLoS Genet 2:e69PubMedCrossRefGoogle Scholar
  18. Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R, Gladyshev VN (2003) Characterization of mammalian selenoproteomes. Science 300:1439–1443PubMedCrossRefGoogle Scholar
  19. Kunsch C, Medford RM (1999) Oxidative stress as a regulator of gene expression in the vasculature. Circ Res 85:753–766PubMedGoogle Scholar
  20. Mendelsohn ME, Karas RH (2005) Molecular and cellular basis of cardiovascular gender differences. Science 308:1583–1587PubMedCrossRefGoogle Scholar
  21. Méplan C, Crosley LK, Nicol F, Beckett GJ, Howie AF, Hill KE, Horgan G, Mathers JC, Arthur JR, Hesketh JE (2007) Genetic polymorphisms in the human selenoprotein P gene determine the response of selenoprotein markers to selenium supplementation in a gender-specific manner (the SELGEN study). Faseb J. doi: 10.1096/fj.07-8166com
  22. Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769PubMedCrossRefGoogle Scholar
  23. Prentice RL (1986) A case-cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika 73:1–11CrossRefGoogle Scholar
  24. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, Gonzalez JR, Gratacos M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME (2006) Global variation in copy number in the human genome. Nature 444:444–454PubMedCrossRefGoogle Scholar
  25. Riese C, Michaelis M, Mentrup B, Gotz F, Kohrle J, Schweizer U, Schomburg L (2006) Selenium-dependent pre- and posttranscriptional mechanisms are responsible for sexual dimorphic expression of selenoproteins in murine tissues. Endocrinology en.2006–0689Google Scholar
  26. Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126PubMedCrossRefGoogle Scholar
  27. Salomaa V, Miettinen H, Kuulasmaa K, Niemela M, Ketonen M, Vuorenmaa T, Lehto S, Palomaki P, Mahonen M, Immonen-Raiha P, Arstila M, Kaarsalo E, Mustaniemi H, Torppa J, Tuomilehto J, Puska P, Pyorala K (1996) Decline of coronary heart disease mortality in Finland during 1983 to 1992: roles of incidence, recurrence, and case-fatality: The FINMONICA MI Register Study, vol 94, pp 3130–3137Google Scholar
  28. Salomaa V, Ketonen M, Koukkunen H, Immonen-Raiha P, Jerkkola T, Karja-Koskenkari P, Mahonen M, Niemela M, Kuulasmaa K, Palomaki P, Arstila M, Vuorenmaa T, Lehtonen A, Lehto S, Miettinen H, Torppa J, Tuomilehto J, Kesaniemi YA, Pyorala K (2003) Trends in coronary events in Finland during 1983–1997. The FINAMI study. Eur Heart J 24:311–319PubMedCrossRefGoogle Scholar
  29. Silander K, Komulainen K, Ellonen P, Jussila M, Alanne M, Levander M, Tainola P, Kuulasmaa K, Salomaa V, Perola M, Peltonen L, Saarela J (2005) Evaluating whole genome amplification via multiply-primed rolling circle amplification for SNP genotyping of samples with low DNA yield. Twin Res Hum Genet 8:368–375PubMedCrossRefGoogle Scholar
  30. Sivenius J, Tuomilehto J, Immonen-Raiha P, Kaarisalo M, Sarti C, Torppa J, Kuulasmaa K, Mahonen M, Lehtonen A, Salomaa V (2004) Continuous 15-year decrease in incidence and mortality of stroke in Finland: the FINSTROKE study. Stroke 35:420–425PubMedCrossRefGoogle Scholar
  31. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–89PubMedCrossRefGoogle Scholar
  32. The International HapMap Consortium (2003) The International HapMap Project. Nature 426:789–796CrossRefGoogle Scholar
  33. Tunstall-Pedoe H (ed) (2003) MONICA monograph and Multimedia Sourcebook. World Health Organization, Geneva, p 244Google Scholar
  34. Tuomisto K, Jousilahti P, Sundvall J, Pajunen P, Salomaa V (2006) C-reactive protein, interleukin-6 and tumor necrosis factor alpha as predictors of incident coronary and cardiovascular events and total mortality. A population-based, prospective study. Thromb Haemost 95:511–518PubMedGoogle Scholar
  35. Vandenplas S, Wiid I, Grobler-Rabie A, Brebner K, Ricketts M, Wallis G, Bester A, Boyd C, Mathew C (1984) Blot hybridisation analysis of genomic DNA. J Med Genet 21:164–172PubMedCrossRefGoogle Scholar
  36. Vartiainen E, Jousilahti P, Alfthan G, Sundvall J, Pietinen P, Puska P (2000) Cardiovascular risk factor changes in Finland 1972–1997. Int J Epidemiol 29:49–56PubMedCrossRefGoogle Scholar
  37. Walder K, Kantham L, McMillan JS, Trevaskis J, Kerr L, De Silva A, Sunderland T, Godde N, Gao Y, Bishara N, Windmill K, Tenne-Brown J, Augert G, Zimmet PZ, Collier GR (2002) Tanis: a link between type 2 diabetes and inflammation? Diabetes 51:1859–1866PubMedCrossRefGoogle Scholar
  38. Weiss LA, Pan L, Abney M, Ober C (2006) The sex-specific genetic architecture of quantitative traits in humans. Nat Genet 38:218–222PubMedCrossRefGoogle Scholar
  39. Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA (2004) A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429:841–847PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Mervi Alanne
    • 1
    Email author
  • Kati Kristiansson
    • 2
  • Kirsi Auro
    • 2
  • Kaisa Silander
    • 2
  • Kari Kuulasmaa
    • 3
  • Leena Peltonen
    • 2
    • 4
    • 5
  • Veikko Salomaa
    • 3
  • Markus Perola
    • 2
    • 4
  1. 1.Department of Molecular MedicineKTL-National Public Health Institute, BiomedicumHelsinkiFinland
  2. 2.Department of Molecular MedicineKTL-National Public Health InstituteHelsinkiFinland
  3. 3.Department of Health Promotion and Chronic Disease PreventionKTL-National Public Health InstituteHelsinkiFinland
  4. 4.Faculty of Medicine, Department of Medical GeneticsUniversity of HelsinkiHelsinkiFinland
  5. 5.The Broad InstituteMassachusetts Institute of TechnologyBostonUSA

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