Abstract
SummaryBackgroundApolipoprotein 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.MethodsData 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.FindingsIn 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.InterpretationHigher apoB shortens lifespan, increases risks of heart disease and stroke, and in multivariable analyses that account for LDL cholesterol, increases risk of diabetes.FundingBritish Heart Foundation, UK Medical Research Council, and UK Research and Innovation.
Highlights
Blood lipid concentrations have an important role in major vascular diseases, including coronary heart disease and stroke.[1]
Multiple sources of evidence show that the number of atherogenic lipoprotein particles, as estimated by apolipoprotein B, is a more accurate measure of the risk that lipoprotein lipids pose than the concentration of cholesterol that they contain, as estimated by either LDL cholesterol or non-HDL cholesterol.[5,6,7,8]
To replicate the findings identified for lifespan and type 2 diabetes, we did a conventional two-sample mendelian randomisation analysis in which SNPs for exposures were derived from UK Biobank participants and SNPs for lifespan and type 2 diabetes were derived from DIAMANTE, a previous large-scale genome-wide association study (GWAS).[17,18]
Summary
Blood lipid concentrations have an important role in major vascular diseases, including coronary heart disease and stroke.[1]. The crucial role of apoB in coronary heart disease is increasingly emerging,[5] the comparative importance of apoB versus LDL cholesterol or triglycerides in other diseases remains less clear. We explore a broad repertoire of outcomes, taking advantage of events reported in first-degree relatives in UK Biobank. In studies using outcomes in first-degree relatives, the genetic instrument is constructed in Lancet Healthy Longev 2021; 2: e317–26
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