Login to view PhD Thesis

Enter your username and password here in order to log in on the website:


Forgot your password?

Genetic variation related to high-density lipoprotein metabolism and risk of coronary heart disease metabolism and risk of coronary heart disease metabolism and risk of coronary heart disease

Maiken Karoline Jensen

Summary

Much research effort has sought to locate the specific genetic variants that may underlie the heredity in coronary heart disease (CHD) shown in family and twin studies. In candidate gene association studies, variations in genes that are known to be involved in biologic pathways of interest to the etiology of the disease are explored. 

Based on the epidemiological observation of an inverse association between high-density lipoprotein (HDL)-cholesterol and risk of CHD, the aim of the present thesis was to investigate if genetic variants that are implicated in the metabolism of HDL were associated with the risk of CHD. Gene-environment interactions, for which there was a strong biological rationale, were also explored. 

Four genes that play a major role in the modulation of the HDL particle were chosen. ABCA1: mediates the cholesterol efflux from cells to lipid-poor apolipoprotein AI; CETP: transfers cholesterol between HDL and apolipoprotein B-containing lipoproteins; LPL: hydrolyzes triglycerides and makes apolipoproteins available for HDL; LIPG: hydrolyzes phospholipids carried by HDL. One to five polymorphisms in each gene were selected and genotyped in smaller casecontrol studies nested within prospective cohort studies in US and Denmark. Plasma lipid and lipoprotein concentrations and risk of CHD were investigated according to genotype and in combination with environmental factors. 

Among five variants in ABCA1, one promoter variant (-565T/C) was associated with risk of CHD, without any pronounced association with HDL-cholesterol concentration. The TaqIB variant in CETP was associated with HDL-cholesterol, but not with CHD-risk. This variant appeared to modify the inverse association between alcohol consumption and risk of CHD, such that only moderate alcohol drinkers who were carriers of the variant allele had a lower risk of CHD. The S447X variant in the LPL gene was associated with lower plasma triglycerides, higher HDLcholesterol, and a lower risk of CHD. Three polymorphisms in the LIPG gene were not statistically significantly associated with plasma HDL-cholesterol concentration and only weak associations with CHD were observed. 

In conclusion, these candidate gene association studies show moderate support for a role of the selected genetic variants in relation to HDL-cholesterol and risk of CHD. The genetic variants that were associated with CHD were generally not associated with HDL-cholesterol concentration. The studied genetic variants may be associated with CHD through a different pathway or measurements of HDL-cholesterol in plasma may not reflect the antiatherogenic properties of the HDL particle well. Improved measures of tissue-specific cholesterol efflux are of great scientific interest for the further exploration of the role HDL metabolism to atherogenesis using the genetic epidemiologic approach.