Humphries, SE and Fisher, RM and Miller, G and Ye, S and Henney, A and Talmud, PJ (1998) Predisposing genes, high-risk environments and coronary artery disease: LPL and MMP-3 as examples. In: Jacotot, B and Mathe, D and Fruchart, JC, (eds.) ATHEROSCLEROSIS XI. (pp. 1055 - 1059). ELSEVIER SCIENCE BV
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Two examples of the modifying effects of environment on genotype on the development of coronary artery disease (CAD) will be presented. Two mutations in the LPL gene (D9N and N291S) have been identified that occur at a combined frequency of 4 - 6% in the general population resulting in a moderate reduction in the LPL activity/mass in vitro. Carriers have slightly elevated plasma TG and lower HDL-C levels, and when compounded by obesity show increased levels of plasma lipid increasing CAD risk. Abnormal matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of coronary atherosclerosis. A common sequence variant, 6As or 5As in the MMP-3 gene promoter, was identified. In patients with lipid levels lowered by treatment, the 5A/6A genotype had no effect on disease progression, but in 6A homozygous individuals whose lipid levels remained high, a significant progression of angiographic stenosis was observed. In vitro, compared to the 5A allele, the 6A promoter had a 2-fold lower strength. Low levels of stromelysin may thus predispose to matrix accumulation and progression of disease, but this may only be clinically important when the individual is also in a high-risk environment such as hyperlipidaemia.
|Title:||Predisposing genes, high-risk environments and coronary artery disease: LPL and MMP-3 as examples|
|Event:||11th International Symposium on Atherosclerosis|
|Dates:||1997-10-05 - 1997-10-09|
|Keywords:||gene-environment interaction plaque, lipoprotein lipase, stromelysin (MMP-3), triglycerides|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science|
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