Abstract for presentation at 11th International Congress of Human Genetics

Selenoprotein S is associated to coronary heart disease in two independent prospectively followed cohorts

  • Mervi Alanne, National Public Health Institute - KTL, department of Molecular Medicine, Finland
  • Kati Komulainen, National Public Health Institute - KTL, department of Molecular Medicine, Finland
  • Kirsi Auro, National Public Health Institute - KTL, department of Molecular Medicine, Finland
  • Leena Peltonen, National Public Health Institute - KTL, department of Molecular Medicine, Finland
  • Kaisa Silander, National Public Health Institute - KTL, department of Molecular Medicine, Finland
  • Veikko Salomaa, National Public Health Institute - KTL, department of Epidemiology and Health Promotion, Finland
  • Markus Perola, National Public Health Institute - KTL, department of Molecular Medicine, Finland

    • Selenoprotein S (SEPS1, chr 15q26.3) has recently been suggested as a candidate gene for traits related to inflammation such as diabetes mellitus and coronary heart disease. SEPS1 functions in endoplasmic reticulum regulating the redox balance and processing misfolded proteins. Its impairment leads to increased expression of cytokines TNF-alpha and IL6. We investigated the role of SEPS1 in cardiovascular disease in two Finnish population-based cohorts (total of 14140 individuals, recruited and sampled in five-year intervals on the years 1992 and 1997), that were both followed-up for disease endpoints. We selected two independent case-cohort samples (FINRISK 92 (n=1002), FINRISK 97 (n=1223)) for genotyping and the results were analysed with Cox’s proportional hazards model.
    To capture the variation in the SEPS1 gene region we selected a dense set of SNPs (5 SNPs over 11 kb region) according to previous association reports, haplotype block status and position. In time-to-event analysis stratified by geographical area and adjusted for relevant CVD risk factors, a SNP located in the upstream region of the gene was associated to higher risk of coronary heart disease events in females in both FINRISK cohorts (hazard ratio, HR 6.5 (1.4-30.5), p=0.019 and HR 3.8 (1.2-12.3), p=0.026, respectively) and in joint analysis in females (HR 3.0 (1.4-6.4), p=0.006). No associations were observed in males. The variant in question is located 2 kb upstream from the transcription start site and has a minor allele frequency of 0.3.
    These results show that SEPS1 is a strong candidate gene for modifying individual’s risk of CHD. A prospective study is free from many biases usually complicating the interpretation of genetic epidemiological studies, which often are cross-sectional in nature. Our results were consistent in two independent large Finnish cohorts, which adds confidence in the findings.

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