Causal evidence for an ApoB-independent metabolomic risk profile associated with coronary artery disease

Background and aims1-H nuclear magnetic resonance (1H-NMR) metabolomic measures in plasma have yielded significant insight into the pathophysiology of cardiometabolic disease, but their interrelated nature complicates causal inference and clinical interpretation. This study aimed to investigate the associations of unrelated 1H-NMR metabolomic profiles with coronary artery disease (CAD), type 2 diabetes (T2D) and ischemic stroke (ISTR). MethodsPrincipal component (PC) analysis was performed on 168 1H-NMR metabolomic measures in 56,712 unrelated European participants from UK Biobank to retrieve unrelated PCs, which were used in multivariable-adjusted cox-proportional hazard models and genome-wide association analyses for Mendelian Randomization (MR). Two-sample MR analyses were conducted in three non-overlapping databases which were subsequently meta-analysed, resulting in combined sample sizes of 755,481 (128,728 cases), 1,017,097 (121,977 cases), and 1,002,264 (56,067 cases) for CAD, T2D, and ISTR, respectively. ResultsWe identified six PCs which collectively explained 88% of the total variance. For CAD in particular, results from both multivariable-adjusted and MR analyses were generally directionally consistent. The pooled odds ratios (ORs) [95% CI] of per one-SD increase in genetically-influenced PC1 and PC3 (both characterized by distinct ApoB-associated lipoprotein profiles) were 1.04 [1.03, 1.05] and 0.94 [0.93, 0.96], respectively. In addition, the pooled OR for CAD of PC4, characterized by simultaneously decreased small HDL and increased large HDL, and independent of ApoB, was 1.05 [1.03, 1.07]. For the other outcomes, PC5 (characterized by increased amino acids) was associated with a higher risk of T2D and ISTR. ConclusionsThis study highlights the existence of an ApoB-independent lipoprotein profile driving CAD. Interestingly, this profile is characterized by a distinctive HDL sub-particle distribution, providing evidence for a role of HDL in the development of CAD.