@phdthesis{discovery10149277,
           month = {May},
            year = {2022},
          school = {UCL (University College London)},
           title = {Investigating the role of triglycerides and triglyceride-containing lipoproteins in cardiovascular disease, using observational and genetic epidemiological methods},
            note = {Copyright {\copyright} The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author's request.},
        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.},
             url = {https://discovery.ucl.ac.uk/id/eprint/10149277/},
          author = {Joshi, Roshni}
}