Variation in the selenoprotein S gene locus is associated with coronary heart disease and ischemic stroke in two independent Finnish cohorts
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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.
KeywordsIschemic Stroke Endoplasmic Reticulum Stress Minor Allele SEPS1 Gene SEPS1 Locus
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 (http://www.genomeutwin.org), 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).
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Tunstall-Pedoe H (ed) (2003) MONICA monograph and Multimedia Sourcebook. World Health Organization, Geneva, p 244Google Scholar