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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, 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, The Lancet Healthy Longevity, Volume 2, Issue 6, 2021, Pages e317-e326, ISSN 2666-7568,

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

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Author: Richardson, Tom G.1; Wang, Qin1,2,3,4; Sanderson, Eleanor1;
Organizations: 1Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
2Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
3Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
4Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
5Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
6Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK
7Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
8Center for Life Course Health Research, University of Oulu, Oulu, Finland
9NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
10Department of Medicine, McGill University, Montreal, QC, Canada
11Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.6 MB)
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Language: English
Published: Elsevier, 2021
Publish Date: 2022-01-17


Background: Apolipoprotein B (apoB) is emerging as the crucial lipoprotein trait for the role of lipoprotein lipids in the aetiology of coronary heart disease. In this study, we evaluated the effects of genetically predicted apoB on outcomes in first-degree relatives.

Methods: Data on lipoprotein lipids and disease outcomes in first-degree relatives were obtained from the UK Biobank study. We did a univariable mendelian randomisation analysis using a weighted genetic instrument for apoB. For outcomes with which apoB was associated at a false discovery rate (FDR) of less than 5%, multivariable mendelian randomisation analyses were done, including genetic instruments for LDL cholesterol and triglycerides. Associations between apoB and self-reported outcomes in first-degree relatives were characterised for 12 diseases (including heart disease, stroke, and hypertension) and parental vital status together with age at death. Estimates were inferred causal effects per 1 SD elevated lipoprotein trait (for apoB, 1 SD=0·24 g/L). Replication of estimates for lifespan and type 2 diabetes was done using conventional two-sample mendelian randomisation with summary estimates from genome-wide association study consortia.

Findings: In univariable mendelian randomisation, genetically elevated apoB in participants was identified to lead to a shorter lifespan in parents (fathers: 0·89 years of life lost per 1 SD higher apoB in offspring, 95% CI 0·63–1·16, FDR-adjusted p=4·0 × 10⁻¹⁰; mothers: 0·48 years of life lost per 1 SD higher apoB in offspring, 0·25–0·71, FDR-adjusted p=1·7 × 10⁻⁴). The effects were strengthened to around 2 years of life lost in multivariable mendelian randomisation and were replicated in conventional two-sample mendelian randomisation (odds ratio [OR] of surviving to the 90th centile of lifespan: 0·38 per 1 SD higher apoB in offspring, 95% CI 0·22–0·65). Genetically elevated apoB caused higher risks of heart disease in all first-degree relatives and a higher risk of stroke in mothers. Findings in first-degree relatives were replicated in two-sample multivariable mendelian randomisation, which identified apoB to increase (OR 2·32 per 1 SD higher apoB, 95% CI 1·49–3·61) and LDL cholesterol to decrease (0·34 per 1 SD higher LDL cholesterol, 0·21–0·54) the risk of type 2 diabetes.

Interpretation: Higher apoB shortens lifespan, increases risks of heart disease and stroke, and in multivariable analyses that account for LDL cholesterol, increases risk of diabetes.

Funding: British Heart Foundation, UK Medical Research Council, and UK Research and Innovation.

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Series: The Lancet. Healthy longevity
ISSN: 2666-7568
ISSN-E: 2666-7568
ISSN-L: 2666-7568
Volume: 2
Issue: 6
Pages: e317 - e326
DOI: 10.1016/S2666-7568(21)00086-6
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: QW is supported by a postdoctoral fellowship from the Novo Nordisk Foundation (NNF17OC0027034). TMF has received funding from the Medical Research Council, MR/T002239/1, and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 875534. This Joint Undertaking received support from the EU Horizon 2020 research and innovation programme, European Federation of Pharmaceutical Industries and Associations, T1D Exchange, Juvenile Diabetes Research Foundation, and Obesity Action Coalition. MIM was a Wellcome Investigator supported by Wellcome funding (098381, 106130, 203141, 212259). MA-K is supported by a research grant from the Sigrid Juselius Foundation, Finland. MVH works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. GDS and TGR work within the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1). The views expressed in this Article are those of the author(s) and not necessarily those of the UK National Health Service, the NIHR, or the Department of Health and Social Care.
Copyright information: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.