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

Abstract BackgroundApolipoprotein B (apoB) is emerging as the lipoprotein entity that is critical for the role that lipoprotein lipids play in the aetiology of coronary heart disease (CHD). In this study, we explored effects of genetically-predicted apoB on endpoints in first-degree relatives. MethodsUnivariable Mendelian randomization (MR) used a weighted genetic instrument (229 SNPs) for apoB. For endpoints that apoB associated with at FDR <5%, multivariable MR analyses including genetic instruments for LDL-C and triglycerides. Estimates are inferred causal effects per 1-SD elevated lipoprotein trait (for apoB, 1-SD= 0.24 g/L). Replication of estimates for longevity and T2D was conducted using conventional two-sample MR using summary estimates from GWAS consortia. FindingsParents were less likely to be alive with 10.7 months of life lost in fathers (95%CI: 7.6, 13.9; FDR-adjusted P=4.0×10?10) and 5.8 months of life lost in mothers (95%CI: 3.0, 8.52; FDR-adjusted P=1.7×10?4) per 1-SD higher apoB in offspring. Effects strengthened to ～2 yrs of life lost in multivariable MR and replicated in conventional two-sample MR (OR surviving to 90th centile: 0.38; 95%CI: 0.22, 0.65). Genetically-elevated apoB caused higher risks of heart disease in all first-degree relatives and higher risk of stroke in mothers.Findings in first-degree relatives were replicated in two-sample multivariable MR which identified apoB to increase (OR 2.32; 95%CI: 1.49, 3.61) and LDL-C lower (OR 0.34; 95%CI: 0.21, 0.54) risk of T2D. InterpretationHigher apoB shortens the lifespan, and increases risks of heart disease and stroke. T2D effects may represent injurious effects of dyslipidaemia to pancreatic islets. Research in ContextEvidence before this studyPrior observational and Mendelian randomization studies have indicated that circulating concentrations of apoB are of critical importance to lipid-mediated atherogenesis, manifest as coronary heart disease.Added value of this studyIn this study, we explored the effects of genetically-predicted elevations in apoB on multiple endpoints occuring in first degree relatives including longevity and sought replication of findings using more conventional methods to exploit the statistical power from data available in large-scale GWAS consortia. We identified that apoB had a deleterious effect on longevity, shortening the lifespan by months to years. Furthermore, apoB caused higher risks of CHD and stroke in first degree relatives. Finally, apoB was identified to increase risk of T2D, in contradistinction to LDL-C which lowered risk of T2D, when employing multivairable MR methods.Implications of all the available evidenceOur findings support apoB as being the major lipoprotein entity critical for CHD and stroke and extends this to identify higher apoB as negatively impacting longevity and increasing risk of T2D. These findings highlight the critical role of apoB in causing cardiometabolic disease, which collectively shortens the lifespan.