Apolipoprotein B underlies the causal relationship of circulating blood lipids with coronary heart disease

Background Circulating blood lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. We sought to explore the causal relationships of blood lipid traits with risk of CHD using multivariable Mendelian randomization. Methods We conducted GWAS of circulating blood lipid traits in UK Biobank (up to n=440,546) for LDL cholesterol, triglycerides and apolipoprotein B to identify lipid-associated SNPs. Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable Mendelian randomization (MR) analyses. Similar analyses were conducted for HDL cholesterol and apolipoprotein A-I. Findings GWAS identified multiple independent SNPs associated at P<5×10 −8 for LDL cholesterol (220), apolipoprotein B (n=255), triglycerides (440), HDL cholesterol (534) and apolipoprotein AI (440). Between 56-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWAS. Almost half (46%) of these SNPs were associated at P<5×10 −8 with more than one lipid related trait. Assessed individually using MR, each of LDL cholesterol (OR 1.66 per 1 standard deviation higher trait; 95%CI: 1.49; 1.86; P=2.4×10 −19 ), triglycerides (OR 1.34; 95%CI: 1.25, 1.44; P=9.1×10 −16 ) and apolipoprotein B (OR 1.73; 95%CI: 1.56, 1.91; P=1.5×10 −25 ) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95%CI: 1.31, 2.81; P=7.5×10 −4 ) retained a robust effect with the estimate for LDL cholesterol (OR 0.85; 95%CI: 0.57; 1.27; P=0.44) reversing and that of triglycerides (OR 1.12; 95%CI: 1.02, 1.23; P=0.01) becoming markedly weaker. Individual MR analyses showed a 1-SD higher HDL-C (OR 0.80; 95%CI: 0.75, 0.86; P=1.7×10 −10 ) and apolipoprotein A-I (OR 0.83; 95%CI: 0.77, 0.89; P=1.0×10 −6 ) to lower the risk of CHD but these effect estimates weakened to include the null on accounting for apolipoprotein B. Conclusions Apolipoprotein B is of fundamental causal relevance in the aetiology of CHD, and underlies the relationship of LDL cholesterol and triglycerides with CHD.