Biomedical consequences of elevated cholesterol-containing lipoproteins and apolipoproteins on cardiovascular and non-cardiovascular outcomes

Background Higher concentrations of cholesterol-containing low-density lipoprotein (LDL-C) increase the risk of cardiovascular disease (CVD). The association of LDL-C with non-CVD traits remains unclear, as are the possible independent contributions of other cholesterol-containing lipoproteins and apolipoproteins. Methods Nuclear magnetic resonance spectroscopy was used to measure the cholesterol content of high density (HDL-C), very low-density (VLDL-C), intermediate-density (IDL-C), as well as low-density lipoprotein fractions, the apolipoproteins Apo-A1 and Apo-B, as well as total triglycerides (TG), remnant-cholesterol (Rem-Chol) and total cholesterol (TC). The causal effects of these exposures were assessed against 33 outcomes using univariable and multivariable Mendelian randomization (MR). Results The majority of cholesterol containing lipoproteins and apolipoproteins affect coronary heart disease (CHD), carotid intima-media thickness, carotid plaque, C-reactive protein (CRP) and blood pressure. Multivariable MR indicated that many of these effects act independently of HDL-C, LDL-C and TG, the most frequently measured lipid fractions. Higher concentrations of TG, VLDL-C, Rem-Chol and Apo-B increased heart failure (HF) risk; often independently of LDL-C, HDL-C or TG. Finally, a subset of these exposures associated with non-CVD traits such as Alzheimer’s disease (AD: HDL-C, LDL-C, IDL-C, Apo-B), type 2 diabetes (T2DM: VLDL-C, IDL-C, LDL-C), and inflammatory bowel disease (IBD: LDL-C, IDL-C). Conclusions The cholesterol content of a wide range of lipoprotein and apolipoproteins associate with measures of atherosclerosis, blood pressure, CRP, and CHD, with a subset affecting HF, T2DM, AD and IBD risk. Many of the observed effects appear to act independently of LDL-C, HDL-C, and TG, supporting the targeting of lipid fractions beyond LDL-C for disease prevention. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government and the British Heart Foundation. AFS is supported by British Heart Foundation (BHF) grant PG/18/5033837, PG/22/10989 and the UCL BHF Research Accelerator AA/18/6/34223. CF and AFS received additional support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. MGM is supported by a BHF Fellowship FS/17/70/33482. ADH and DAL (NF-0616-10102) are an NIHR Senior Investigators. This work was funded by the Strategic Priority Fund “Tackling multimorbidity at scale” programme [MR/V033867/1] delivered by the Medical Research Council and the National Institute for Health and Care Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council. The UCLEB Consortium is supported by a British Heart Foundation Programme Grant (RG/10/12/28456). DAL’s contribution to this research is supported by the Bristol BHF Accelerator Award (AA/18/1/34219), her BHF Chair (CH/F/20/90003) and the UK Medical Research Council (MC_UU_00011/1-6). MK is supported by the UK Medical Research Council (MRC MR/R024227/1), National Institute on Aging (NIA), US (R01AG056477), and the Wellcome Trust (221854/Z/20/Z). PC is supported by the Thailand Research Fund (MRG6280088). TRG receives funding from the UK Medical Research Council as part of the MRC Integrative Epidemiology Unit (MC_UU_00011/4). AH receives support from the British Heart Foundation (SP/F/21/150020) and UK Medical Research Council (MC_PC-20051). ADH receives support from the UK Medical Research Council (MC_UU_12019/1). NF received funding from the National Health Institutes (MD012765, DK117445). CG has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 754490—MINDED project.