The key role of apolipoprotein B in major vascular diseases and longevity
Authors: Petroula Proitsi
Journal: The Lancet Healthy Longevity (2021)

Disentangling the causal role of blood lipids in the aetiology of major vascular diseases is of critical importance because it can fill knowledge gaps about underlying pathophysiological mechanisms and provide a powerful roadmap for therapeutic interventions. The importance of apopolipoprotein B (apoB) in major vascular diseases has become increasingly clear. ApoB is the main structural component of atherogenic lipoproteins, and each lipoprotein contains a single molecule of apoB. ApoB therefore represents a direct measure of the total atherogenic particles in the circulation that can enter the arterial wall, and is a more accurate measure of the risk posed by these particles than the mass of cholesterol they contain, estimated by LDL cholesterol or non-HDL cholesterol.1Sniderman AD Thanassoulis G Glavinovic T et al.Apolipoprotein B particles and cardiovascular disease: a narrative review.JAMA Cardiol. 2019; 4: 1287-1295Crossref PubMed Scopus (72) Google Scholar Indeed, apoB has been shown to predominantly account for the association of lipoprotein lipids with risk of coronary heart disease2Richardson TG Sanderson E Palmer TM et al.Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable Mendelian randomisation analysis.PLoS Med. 2020; 17e1003062Crossref PubMed Google Scholar, 3Zuber V Gill D Ala-Korpela M et al.High-throughput multivariable mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease.Int J Epidemiol. 2020; (published online Nov 1.)https://doi.org/10.1093/ije/dyaa216PubMed Google Scholar and stroke.4Yuan S Tang B Zheng J Larsson SC Circulating lipoprotein lipids, apolipoproteins and ischemic stroke.Ann Neurol. 2020; 88: 1229-1236Crossref PubMed Scopus (8) Google Scholar Nevertheless, the importance of apoB in other major diseases and for longevity, especially when taking into consideration LDL cholesterol or triglycerides, has not been systematically investigated. In an important and well designed study in The Lancet Healthy Longevity, Tom Richardson and colleagues5Richardson TG Wang Q Sanderson E et al.Effects of apolipoprotein B on lifespan and risks of major diseases including type 2 diabetes: a mendelian randomisation analysis using outcomes in first-degree relatives.Lancet Healthy Longev. 2021; (published online May 20)https://doi.org/10.1016/S2666-7568(21)00086-6Summary Full Text Full Text PDF Scopus (1) Google Scholar explore the effects of apoB on 12 health outcomes, including coronary heart disease, type 2 diabetes, and stroke, as well as longevity and vital status. The study exploited the power of a large dataset, the UK Biobank, with information on outcomes in first-degree relatives of participants used as a proxy for diagnosis, and a powerful statistical approach, using mendelian randomisation, which assesses the causal effect of a risk factor on an outcome. The authors then scrutinised the comparative role of apoB versus LDL cholesterol and triglycerides by doing multivariable mendelian randomisation, an extension of mendelian randomisation that simultaneously estimates the causal effect of each risk factor on the outcome, and replicated their main findings using two independent, large-scale genome-wide association consortia. The study had sufficient power and a series of sensitivity analyses were done. The findings are noteworthy. Genetically determined increase of apoB had a negative effect on longevity, with higher apoB associated with decreased lifespan and younger age at death in first-degree relatives. When the effects of LDL cholesterol and triglycerides were taken into consideration, the effect of apoB strengthened, highlighting apoB as the predominant trait affecting lifespan. These observations were replicated in an independent dataset that did not use outcomes in first-degree relatives. Higher apoB was also associated with higher risks of coronary heart disease and stroke, as previously reported.2Richardson TG Sanderson E Palmer TM et al.Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable Mendelian randomisation analysis.PLoS Med. 2020; 17e1003062Crossref PubMed Google Scholar, 3Zuber V Gill D Ala-Korpela M et al.High-throughput multivariable mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease.Int J Epidemiol. 2020; (published online Nov 1.)https://doi.org/10.1093/ije/dyaa216PubMed Google Scholar, 4Yuan S Tang B Zheng J Larsson SC Circulating lipoprotein lipids, apolipoproteins and ischemic stroke.Ann Neurol. 2020; 88: 1229-1236Crossref PubMed Scopus (8) Google Scholar As the authors note, these results do not downplay the role of LDL cholesterol and triglycerides, but rather underline that apoB is necessary for them to exert their causal effects,5Richardson TG Wang Q Sanderson E et al.Effects of apolipoprotein B on lifespan and risks of major diseases including type 2 diabetes: a mendelian randomisation analysis using outcomes in first-degree relatives.Lancet Healthy Longev. 2021; (published online May 20)https://doi.org/10.1016/S2666-7568(21)00086-6Summary Full Text Full Text PDF Scopus (1) Google Scholar, 6Sniderman AD Pencina M Thanassoulis G ApoB: the power of physiology to transform the prevention of cardiovascular disease.Circ Res. 2019; 124: 1425-1427Crossref PubMed Scopus (14) Google Scholar through the entrapment of apoB within the arterial wall. All of these findings highlight the importance of measuring apoB in addition to the standard lipid panel in routine clinical practice and emphasise the clinical benefit of lowering apoB. A surprising finding was that higher apoB was associated with lower type 2 diabetes risk in first-degree relatives in univariable mendelian randomisation, but higher type 2 diabetes risk in multivariable mendelian randomisation. Overall, although the associations of LDL cholesterol and triglycerides with most outcomes in univariable analyses were similar to the associations seen with apoB, the effects of apoB and LDL cholesterol in multivariable analyses differed for most outcomes. In particular, higher LDL cholesterol was associated with increased longevity and decreased type 2 diabetes risk in multivariable mendelian randomisation. These findings were confirmed in the independent cohorts. Higher LDL cholesterol levels have been previously associated with type 2 diabetes through observational and genetic studies,7Klimentidis YC Arora A Newell M et al.Phenotypic and genetic characterization of lower LDL Cholesterol and increased type 2 diabetes risk in the UK Biobank.Diabetes. 2020; 69: 2194-2205Crossref PubMed Scopus (5) Google Scholar, 8Lotta LA Sharp SJ Burgess S et al.Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis.JAMA. 2016; 316: 1383-1391Crossref PubMed Scopus (207) Google Scholar but the positive causal association of apoB with type 2 diabetes risk in the presence of a negative association of LDL cholesterol and type 2 diabetes risk is novel. The authors discuss the possible physiological mechanisms for these observations and propose that these divergent effects could represent increased uptake of LDL particles by the pancreas, which might lead to injury, resulting in a reduction of β cells in pancreatic islets and higher type 2 diabetes risk. This finding, according to Richardson and colleagues, could have repercussions for treatment strategies that lower the uptake of LDL particles by the pancreas and increase the uptake by the liver, which could result in reducing the risk for both coronary heart disease and type 2 diabetes. Finally, the authors showed that coronary heart disease and type 2 diabetes partially mediated the effects of apoB on longevity, another finding that emphasises the key importance of apoB. As the authors acknowledge, this study has some limitations that are inherent to the UK Biobank data, including self-reporting bias and use of outcomes in first-degree relatives, although the main findings were replicated using independent datasets. Future studies that use approaches addressing the high correlation between the three risk factors (apoB, LDL cholesterol, and triglycerides) would be valuable in confirming findings. It would also be interesting to explore the associations of more detailed lipoprotein subclasses obtained through nuclear magnetic resonance spectroscopy, in addition to the conventional measures that quantify the sum of lipids across lipoproteins, and to reassert the importance of apoB. Finally, future studies should be expanded beyond the UK Biobank. Unravelling the comparative role of lipids and lipoproteins in major vascular disease and longevity is of crucial public health importance because it can pinpoint the appropriate biomarkers for effective lipid-modifying interventions. This study highlights the key role of apoB in longevity and vascular disease and suggests that targeting apoB should be the primary goal of lipid-modifying strategies. I declare no competing interests. Effects of apolipoprotein B on lifespan and risks of major diseases including type 2 diabetes: a mendelian randomisation analysis using outcomes in first-degree relativesHigher apoB shortens lifespan, increases risks of heart disease and stroke, and in multivariable analyses that account for LDL cholesterol, increases risk of diabetes. Full-Text PDF Open Access