Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death

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• 作者：Yue-Mei Fan (1)
  Pekka J Karhunen (2)
  Mari Levula (1)
  Erkki Ilveskoski (2)
  Jussi Mikkelsson (2)
  Olli A Kajander (2)
  Otso J?rvinen (3)
  Niku Oksala (1) (4)
  Janita Thusberg (5)
  Mauno Vihinen (5) (6)
  Juha-Pekka Salenius (4)
  Leena Kyt?m?ki (7)
  Juhani T Soini (7)
  Reijo Laaksonen (1) (6)
  Terho Lehtim?ki (1)
  
• 刊名：Thrombosis Journal
• 出版年：2008
• 出版时间：December 2008
• 年：2008
• 卷：6
• 期：1
• 全文大小：234KB
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• 作者单位：Yue-Mei Fan (1)
  Pekka J Karhunen (2)
  Mari Levula (1)
  Erkki Ilveskoski (2)
  Jussi Mikkelsson (2)
  Olli A Kajander (2)
  Otso J?rvinen (3)
  Niku Oksala (1) (4)
  Janita Thusberg (5)
  Mauno Vihinen (5) (6)
  Juha-Pekka Salenius (4)
  Leena Kyt?m?ki (7)
  Juhani T Soini (7)
  Reijo Laaksonen (1) (6)
  Terho Lehtim?ki (1)
  
  1. Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland
  2. Department of Forensic Medicine, Medical School, University of Tampere, Tampere, Finland
  3. Heart Centre, Department of Cardiac Surgery, Tampere University Hospital, Tampere, Finland
  4. Division of Vascular Surgery, Department of Surgery, Tampere University Hospital, Tampere, Finland
  5. Institute of Medical Technology, University of Tampere, Tampere, Finland
  6. Research Unit, Tampere University Hospital, Tampere, Finland
  7. Turku Centre for Biotechnology, University of Turku and ?bo Akademi University, Turku, Finland
  

文摘

Background Disturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques. Cellular cholesterol homeostasis is controlled by the sterol regulatory element-binding transcription factor 2 (SREBF-2) and the SREBF cleavage-activating protein (SCAP). We investigated whole genome expression in a series of human atherosclerotic samples from different vascular territories and studied whether the non-synonymous coding variants in the interacting domains of two genes, SREBF-2 1784G>C (rs2228314) and SCAP 2386A>G, are related to the progression of coronary atherosclerosis and the risk of pre-hospital sudden cardiac death (SCD). Methods Whole genome expression profiling was completed in twenty vascular samples from carotid, aortic and femoral atherosclerotic plaques and six control samples from internal mammary arteries. Three hundred sudden pre-hospital deaths of middle-aged (33-9 years) Caucasian Finnish men were subjected to detailed autopsy in the Helsinki Sudden Death Study. Coronary narrowing and areas of coronary wall covered with fatty streaks or fibrotic, calcified or complicated lesions were measured and related to the SREBF-2 and SCAP genotypes. Results Whole genome expression profiling showed a significant (p = 0.02) down-regulation of SREBF-2 in atherosclerotic carotid plaques (types IV-V), but not in the aorta or femoral arteries (p = NS for both), as compared with the histologically confirmed non-atherosclerotic tissues. In logistic regression analysis, a significant interaction between the SREBF-2 1784G>C and the SCAP 2386A>G genotype was observed on the risk of SCD (p = 0.046). Men with the SREBF-2 C allele and the SCAP G allele had a significantly increased risk of SCD (OR 2.68, 95% CI 1.07-.71), compared to SCAP AA homologous subjects carrying the SREBF-2 C allele. Furthermore, similar trends for having complicated lesions and for the occurrence of thrombosis were found, although the results were not statistically significant. Conclusion The results suggest that the allelic variants (SREBF-2 1784G>C and SCAP 2386A>G) in the cholesterol homeostasis regulating SREBF-SCAP pathway may contribute to SCD in early middle-aged men.