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Abstract
Lipoprotein subclass concentrations are modifiable markers of cardiovascular disease risk. Fenofibrate is known to show beneficial effects on lipoprotein subclasses, but little is known about the role of genetics in mediating the responses of lipoprotein subclasses to fenofibrate. A recent genomewide association study (GWAS) associated several single nucleotide polymorphisms (SNPs) with lipoprotein measures, and validated these associations in two independent populations. We used this information to construct genetic risk scores (GRSs) for fasting lipoprotein measures at baseline (pre-fenofibrate), and aimed to examine whether these GRSs also associated with the responses of lipoproteins to fenofibrate. Fourteen lipoprotein subclass measures were assayed in 817 men and women before and after a three week fenofibrate trial. We set significance at a Bonferroni corrected alpha <0.05 (p < 0.004). Twelve subclass measures changed with fenofibrate administration (each p = 0.003 to <0.0001). Mixed linear models which controlled for age, sex, body mass index (BMI), smoking status, pedigree and study-center, revealed that GRSs were associated with eight baseline lipoprotein measures (p < 0.004), however no GRS was associated with fenofibrate response. These results suggest that the mechanisms for changes in lipoprotein subclass concentrations with fenofibrate treatment are not mediated by the genetic risk for fasting levels.
Highlights
Lipoproteins within the given fractions of very low-density, low-density, intermediate-density and high-density lipoproteins (VLDL, LDL, intermediate-density lipoproteins (IDL) and HDL respectively) can be further subdivided into small, medium and large subfractions based on size, which partially reflects the lipid and apolipoprotein content of the particle
We saw a significant increase in the average size of LDL particle (p < 0.0001) which resulted from a decrease in the concentration of small LDL (p > 0.0001); the concentration of large LDL did not change (p = 0.19; Table 2)
This study examined whether the change in lipoprotein subclass concentration and distribution after a three week fenofibrate trial was associated with single nucleotide polymorphisms (SNPs) previously identified with fasting Nuclear Magnetic Resonance Spectroscopy (NMR)-measured lipoprotein phenotypes
Summary
Lipoproteins within the given fractions of very low-density, low-density, intermediate-density and high-density lipoproteins (VLDL, LDL, IDL and HDL respectively) can be further subdivided into small, medium and large subfractions based on size, which partially reflects the lipid and apolipoprotein content of the particle. Specific distributions of lipoprotein subfractions, characterized by small LDL and large VLDL and HDL particles, demonstrate associations with disease states such as insulin resistance and atherosclerosis [2,3,4,5,6,7]. NMR measures are currently more expensive to collect than traditional enzymatic lipid measures, future clinical interest in lipoprotein subfractions may lie in the observation that subclass concentrations and distributions are modifiable, changing in response to exercise, diet and pharmacological interventions aimed at reducing atherosclerosis risk [12,13,14,15,16]
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