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.

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

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.

Déclaration de conflit d'intérêts

Declaration of interests TMF reports grants from GlaxoSmithKline, outside the submitted work. MIM has served on advisory panels for Pfizer, Novo Nordisk, and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from AbbVie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. MVH has collaborated with Boehringer Ingelheim in research, and in adherence with the University of Oxford’s Clinical Trial Service Unit & Epidemiological Studies Unit staff policy, did not accept personal honoraria or other payments from pharmaceutical companies. In June, 2019, and January, 2020, respectively, MIM and AM became employees of Genentech and holders of Roche stock. All other authors declare no competing interests.