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

Richardson, Tom G and Sanderson, Eleanor and Palmer, Tom M and Ala-Korpela, Mika and Ference, Brian A and Davey Smith, George and Holmes, Michael V (2019) Apolipoprotein B underlies the causal relationship of circulating blood lipids with coronary heart disease. medRxiv.

Abstract

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<5x10-8 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<5x10-8 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=2.4x10-19), triglycerides (OR 1.34; 95%CI: 1.25, 1.44; P=9.1x10-16) and apolipoprotein B (OR 1.73; 95%CI: 1.56, 1.91; P=1.5x10-25) 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=7.5x10-4) 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=1.7x10-10) and apolipoprotein A-I (OR 0.83; 95%CI: 0.77, 0.89; P=1.0x10-6) 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.Competing Interest StatementBAF reported receiving personal fees from Merck & Co., Amgen, Regeneron, Sanofi, Pfizer, CiVi BioPhama, and KrKA Phamaceuticals, and grants from Merck & Co., Amgen, Novartis and Esperion Therapeutics. All other authors report no potential conflicts of interest. Funding StatementTGR, ES and GDS work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1 and MC_UU-00011/2). TGR is a UKRI Innovation Research Fellow (MR/S003886/1). MAK is supported by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (APP1158958) and a research grant from the Sigrid Juselius Foundation, Finland. The Baker Institute is supported in part by the Victorian Government’s Operational Infrastructure Support Program. BAF is supported by the National Institute for Health Research Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust. 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 Oxford Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author DeclarationsAll relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesAny clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript.Not ApplicableI have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable.Not ApplicableGWAS data will become available once the manuscript is In Press