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APOA1, HDL cholesterol and ischemic heart disease

Christiane Lundegaard Haase

Summary

This PhD thesis is based on studies performed during my employment at the Department of Clinical Biochemistry, Rigshospitalet, in 2008-11. The results are presented in the form of three articles, of which two have been published, and one is submitted. Finally, a review summarizes the results in context of previous studies on APOA1, high-density lipoprotein (HDL) cholesterol and ischemic heart disease (IHD).

Epidemiologic studies show that plasma levels of apolipoprotein A-I (apoA-I) and HDL cholesterol are inversely related to risk of IHD. ApoA-I is the major protein constituent of the HDL particle and is crucial in HDL metabolism. Studies have shown that APOA1 encoding apoA-I is pleoitropic as it affects several phenotypes. APOA1 has been widely used as a candidate gene in genotype-phenotype association studies of lipid and lipoproteins levels and risk of cardiovascular disease presenting conflicting results. Furthermore, genetic variation in APOA1 associates with amyloidosis, which among others may affect heart and arteries. 

The purpose of this PhD thesis was to test the hypotheses that 1) common genetic variation in APOA1 associates with plasma levels of apoA-I and HDL cholesterol, and contributes to risk of IHD consistent with the effects on levels of apoA-I and HDL cholesterol.; 2) rare, structural genetic variation in APOA1 associates with plasma levels of apoA-I and HDL cholesterol, and with risk of IHD and mortality; and 3) the load of genetic variation in APOA1 in the population is relatively high and may contribute to complex traits.

The major findings were that 1) common genetic variation in APOA1 associated with elevated apoA-I and HDL cholesterol levels did not associate with decreased risk of IHD, 2) a rare genetic variant in APOA1, A164S, associated with IHD and mortality without low HDL cholesterol levels, and 3) the burden of genetic variation in APOA1 is relatively high in the general population, and structural genetic variants may contribute to complex traits.