Joshi, Roshni; (2022) Investigating the role of triglycerides and triglyceride-containing lipoproteins in cardiovascular disease, using observational and genetic epidemiological methods. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Despite effective low-density lipoprotein cholesterol (LDL-C) lowering by statins, there remains a residual risk of CVD in individuals, which may in part be due to elevated triglyceride (TG) levels. Existing research evaluating the relationship between triglycerides and CVD has so far been mixed, and therapeutic agents to reduce triglycerides for CVD prevention are not routinely prescribed. Previous studies investigate total serum TG, which represents the summation of TG carried across all lipoproteins. It is possible that certain TG containing lipoproteins are more atherogenic than others, and thus using total serum TG measurement may be insufficiently precise to delineate any causal effect. 1H-nuclear magnetic resonance (NMR) spectroscopy classifies lipoproteins into 14 different lipoprotein subfractions based on size and lipid composition, offering a more detailed interrogation to help confirm or refute the possible causal relationship between TG and CVD. This thesis assesses the distribution of cholesterol and triglyceride content in 14 lipoprotein subfractions and establishes reference interval ranges based on the 2.5th and 97.5th percentiles. The largest interval range for TG content was observed in the medium VLDL subfraction (2.5th 97.5th percentile; 0.08 to 0.68 mmol/L), and for cholesterol content in the large LDL subfraction (0.47-1.45 mmol/L). TG concentrations in all sub-classes increased with increasing age and BMI. Increases in cholesterol concentrations were largely comparable between men and women by age, smoking status, and between fasting and nonfasting states. TG subfraction concentrations were significantly higher in ever smokers compared to never smokers, among subjects with CVD and type 2 diabetes as compared to disease-free subjects. The TG content in the 14 lipoprotein subfractions is evaluated for association with CVD, and the extent to which the effect is independent of LDL-C and HDL-C is explored in observational analysis in Chapter 5. The results in this chapter demonstrate TG in 13 lipoprotein subfractions were positively associated with CHD (OR in the range 1.12 to 1.22). The positive effect estimates attenuated after adjustment for HDL-C and LDL-C. There was an absence of evidence demonstrating any association TG lipoprotein subfraction with stroke. Next, to elucidate potential causal relationships, observational and Mendelian randomisation (MR) approaches are used to investigate the total and direct effects of triglyceride and cholesterol content on CHD. There was a total causal association of TG content in five lipoprotein subfractions, and total association of cholesterol content in 10 lipoprotein subfractions with CHD. Multivariable MR analysis was used to explore the direct effects of TG content of the 14 lipoprotein subfractions conditioning on the cholesterol content, and vice versa for cholesterol associations. Here we found that there was a direct association of CHD for TG in four lipoprotein subfractions and cholesterol in 10 lipoprotein subfractions. Cholesterol content in triglyceride-rich lipoproteins (TRL) displayed the largest effects (MVMR OR in the range 2.73 to 14.31), an association that was not observed for TG in TRL. The observational and MR associations between TG content in lipoprotein subfractions and CHD presented here may be relevant in the context of ongoing drug development targeting TG-mediated pathways for disease reduction. An emerging approach to lower TG concentrations and lower risk of CHD is through inhibition of LPL function. Angiopoietinlike proteins 3 and 4 (ANGPLT3/4) are negative regulators of LPL and have recently emerged as novel drug targets to manage dyslipidaemia. The final section of this thesis discusses the contribution of the results to the current understanding of role of TG in CVD and translational applications to clinical care.

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