Genetic and environmental determinants of triglyceride levels: ANGPTL4 as a key functional modulator.
Doctoral thesis, UCL (University College London).
Background and Aims: The manifestation of chronic diseases such as cardiovascular disease (CVD) is a consequence of a complex interplay of genetic and environmental factors, of which diet plays an important role. The susceptibility to CVD is partly determined by genetic factors, but a “CVD-promoting environment” may also be necessary for its phenotypic expression. Angiopoietin-like 4 (Angptl4) is a dual-function protein: with the N terminus an inhibitor of lipoprotein lipase (LPL), influencing plasma triglycerides, and a C terminus with potential angiogenic properties. Analysis concentrated on the association of two ANGPTL4 coding SNPs with lipid profiles and CVD risk and associated traits in healthy and diseased individuals from 8 separate cohorts. In vitro studies were performed, to further our understanding of the role of this protein in inter-individual variability in triglyceride levels and in the pathogenesis of coronary heart disease. Results: Data has confirmed a strong association of E40K with triglyceride-lowering in over 13,000 individuals from 5 studies. Effects on HDL-raising in those studies with available measures were equally robust and consistent. However, despite these CHD protective effects there is a borderline association of E40K with increased CHD risk, independent of effects on CHD risk. The association of T266M with triglyceride levels, independent of E40K, was only seen under conditions of post-prandial stress and there was no association with CHD risk. In the Look AHEAD cohort of type II diabetes patients, an association of the ANGPTL4 T266M variant with triglyceride levels at baseline, independent of E40K, was reported for the first time. T266M, but not E40K, was independently associated with Angptl4 levels, yet circulating Angptl4 levels showed no correlation with triglyceride levels. Furthermore, T266M was not associated with CHD risk in meta-analysis. The data suggest that circulating Angptl4 does not reflect what is occurring at the cellular level. The in vitro studies confirmed that E40K is unable to inhibit LPL but T266M does not impair this function of the protein. The T266M variant did however effect secretion of the Angptl4 into the media of HEK-293A and Huh7 cells, highlighting the possibility of T266M as a functional variant and providing a biological basis for the association of T266M with circulating Angplt4 levels. Although this may have little importance in circulation, the effect T266M has on protein secretion may be of great importance in a tissue-specific manner when considering the autocrine and paracrine effect of Angptl4. Conclusions: The association studies and in vitro data from this thesis provide new insights into the role of Angptl4 in triglyceride metabolism.
|Title:||Genetic and environmental determinants of triglyceride levels: ANGPTL4 as a key functional modulator|
|Additional information:||Permission for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Centre for Cardiovascular Genetics|
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