ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 12.14 | DOI: 10.1530/ey.18.12.14

ESPEYB18 12. Obesity and Weight Regulation Lipids (4 abstracts)

12.14. Effects of apolipoprotein B on the lifespan and risks of major disease including type 2 diabetes: a mendelian randomization analysis using outcomes in first-degree relatives

Tom G Richardson , Qin Wang , Eleanor Sanderson , Anubha Mahajan , Mark I McCarthy , Timothy M Frayling , Mika Ala-Korpela , Allan Sniderman , George Davey Smith & Michael V Holmes

Lancet Healthy Longevity 2021 10.1016/S2666-7568(21)00086-6.

In brief: Using a multivariable Mendelian randomization approach, genetic data on lipoprotein lipid levels and disease outcomes indicated that higher Apolipoprotein B (ApoB) levels increase the risks of coronary heart disease, stroke and T2DM, and shorten longevity. ApoB is emerging as a more sensitive measure of disease risks posed by lipoprotein than the conventionally used LDL-C.

Comment: Mendelian randomization is the analytical modelling of selected genetic variants that are randomly distributed at birth, and are known to be reliably associated with a specific risk factor, to obtain causal effect estimates for these risk factors on disease outcomes. Multivariable Mendelian randomization is an extension of the standard Mendelian randomization to consider multiple potential risk factors in a single model.

ApoB is a structural protein that constitutes a major component of the atherogenic lipoproteins: very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL. Each of these lipoprotein particles carries one ApoB molecule. Therefore, ApoB levels reflect the atherogenic potential of these lipoproteins.

The current study investigated the effects of genetically predicted elevations of ApoB on risks of heart disease, stroke, hypertension, Alzheimer's disease, T2DM and lifespan (the last was reported in first degree relatives). Using multivariable Mendelian randomization, the independent effects of ApoB, LDL-C and triglycerides were simultaneously assessed. More than 400 000 participants reported lifespan information on their first-degree relatives.

Higher ApoB was genetically associated with a shorter lifespan of parents and increased risk for stroke and heart disease. The authors concluded that the number of circulating ApoB particles rather than their lipid content is the critical element for atherogenesis. They suggest that reductions in ApoB should be the primary goal of lipid-lowering, not only because this leads to lower risk of common diseases such as heart disease and stroke, but also because reduced ApoB prolongs lifespan by a period of months to years.

Of note, this article was initially published in medRxiv (pronounced “med-archive”) an internet site founded in 2019, which displays complete but non-reviewed and unpublished pre-prints of manuscripts in the areas of medicine, clinical research and related health sciences. medRxiv provides a platform for researchers to share, comment on and receive feedback on their work before journal submission or publication. As the manuscripts are not yet peer reviewed, the site states that the findings should not be considered for clinical application, nor relied upon as established information. medRxiv can save authors time in submitting papers to journals by directly transmitting their manuscript files and metadata. The list of journals that participate is published in

Reference: 1. Fellin R, Manzato E. Lipoprotein-X fifty years after its original discovery. Nutrition, metabolism, and cardiovascular diseases: NMCD. 2019; 29(1): 4–8.2. Vuorio A, Ramaswami U, Holven KB. Editorial: Genetics of Familial Hypercholesterolemia: New Insight. 2021; 12(666).

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